U.S. patent application number 16/619776 was filed with the patent office on 2020-05-07 for gonadotropin-releasing hormone antagonist dosing regimens for the treatment of endometriosis.
The applicant listed for this patent is ObsEva S.A.. Invention is credited to Jean-Pierre GOTTELAND, Ernest LOUMAYE.
Application Number | 20200138819 16/619776 |
Document ID | / |
Family ID | 62620835 |
Filed Date | 2020-05-07 |
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United States Patent
Application |
20200138819 |
Kind Code |
A1 |
LOUMAYE; Ernest ; et
al. |
May 7, 2020 |
GONADOTROPIN-RELEASING HORMONE ANTAGONIST DOSING REGIMENS FOR THE
TREATMENT OF ENDOMETRIOSIS
Abstract
The invention provides methods of treating endometriosis in a
patient by administration of a gonadotropin-releasing hormone
(GnRH) antagonist, for instance, according to dosing regimens
predicated on the patient's level of anti-Mullerian hormone (AMH)
or .beta.17-estradiol (E2).
Inventors: |
LOUMAYE; Ernest; (Cologny,
CH) ; GOTTELAND; Jean-Pierre; (Geneva, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ObsEva S.A. |
Plan-les-Ouates |
|
CH |
|
|
Family ID: |
62620835 |
Appl. No.: |
16/619776 |
Filed: |
June 5, 2018 |
PCT Filed: |
June 5, 2018 |
PCT NO: |
PCT/EP2018/064768 |
371 Date: |
December 5, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62515268 |
Jun 5, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/519 20130101;
A61P 15/00 20180101; A61K 38/09 20130101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 38/09 20060101 A61K038/09; A61P 15/00 20060101
A61P015/00 |
Claims
1. A method of treating endometriosis in a human patient, wherein
the concentration of anti-Mullerian hormone (AMH) in a sample
isolated from said patient has been determined, said method
comprising: a. comparing said concentration of AMH to an AMH
reference range; and b. administering a higher daily dosage and/or
an elevated dosing frequency of a GnRH antagonist to the patient if
the concentration of AMH in the sample isolated from the patient is
above the AMH reference range; or c. administering a lower daily
dosage and/or a reduced dosing frequency of a GnRH antagonist to
the patient if the concentration of AMH in the sample isolated from
the patient is below the AMH reference range.
2. The method of claim 1, said method comprising administering an
intermediate quantity and/or an intermediate dosing frequency of a
GnRH antagonist to the patient if the concentration of AMH in the
sample isolated from the patient is within the AMH reference
range.
3. The method of claim 1 or 2, said method comprising
administering: from 20 to 700 mg/day of the GnRH antagonist to the
patient if the concentration of AMH in the sample isolated from the
patient is above the AMH reference range; from 10 to 500 mg/day of
the GnRH antagonist to the patient if the concentration of AMH in
the sample isolated from said patient is within the AMH reference
range; or from 5 to 400 mg/day of a GnRH antagonist to the patient
if the concentration of AMH in the sample isolated from said
patient is below the AMH reference range.
4. A method of determining a dosing regimen for the treatment of
endometriosis in a human patient, wherein the concentration of AMH
in a sample isolated from said patient has been determined, said
method comprising: a. comparing said concentration of AMH to an AMH
reference range; b. determining that the patient be administered a
higher daily dosage and/or an elevated dosing frequency of a GnRH
antagonist to the patient if the concentration of AMH in the sample
isolated from the patient is above the AMH reference range; c.
determining that the patient be administered a lower daily dosage
and/or a reduced dosing frequency of a GnRH antagonist to the
patient if the concentration of AMH in the sample isolated from the
patient is below the AMH reference range; or d. determining that
the patient be administered an intermediate quantity and/or an
intermediate dosing frequency of a GnRH antagonist to the patient
if the concentration of AMH in the sample isolated from the patient
is within the AMH reference range.
5. The method of any one of claims 1-4, wherein said AMH reference
range is from 15 to 35 pM.
6. The method of any one of claims 1-5, said method comprising
administering said GnRH antagonist to said patient in an amount
sufficient to reduce the serum concentration of .beta.17-estradiol
(E2) in said patient to between about 20 and about 50 pg/ml,
preferably within about 4 to about 36 weeks of said
administering.
7. The method of any one of claims 1-6, said method comprising
administering said GnRH antagonist to said patient in an amount
sufficient to reduce the serum concentration of follicle
stimulating hormone (FSH) in said patient to between about 0.1 and
about 10 mIU/ml, preferably within about 4 to about 36 weeks of
said administering.
8. The method of any one of claims 1-7, said method comprising
administering said GnRH antagonist to said patient in an amount
sufficient to reduce the serum concentration of luteinizing hormone
(LH) in said patient to between about 0.1 and about 10 mIU/ml,
preferably within about 4 to about 36 weeks of said
administering.
9. The method of any one of claims 1-8, said method comprising
administering said GnRH antagonist to said patient in an amount
sufficient to reduce endometriosis-associated pain in said patient,
preferably within about 4 to about 36 weeks of said
administering.
10. The method of claim 9, wherein said endometriosis-associated
pain is selected from the group consisting of pelvic pain,
dyspareunia, and dyschezia.
11. The method of claim 9 or 10, wherein said
endometriosis-associated pain is assessed by determining a
Numerical Rating Score (NRS) for said patient.
12. The method of claim 11, wherein said NRS is reduced by from
about 1% to about 50%.
13. The method of claim 12, wherein said NRS is reduced by about
30%.
14. The method of claim 9 or 10, wherein said
endometriosis-associated pain is assessed by determining a Verbal
Rating Score (VRS) for said patient.
15. The method of claim 14, wherein said VRS is reduced by from
about 1% to about 50%.
16. The method of claim 15, wherein said VRS is reduced by about
30%.
17. The method of any one of claims 1-16, said method comprising
administering said GnRH antagonist to said patient in an amount
sufficient to alleviate a symptom selected from the group
consisting of dysmenorrhea, non-menstrual pelvic pain, and
dyspareunia, preferably within about 4 to about 36 weeks of said
administering.
18. The method of claim 17, wherein said symptom is assessed by
determining a Biberoglu and Behrman (B&B) scale score for said
patient.
19. The method of claim 18, wherein said B&B scale score is
reduced by from about 1% to about 50%.
20. The method of any one of claims 1-19, said method comprising
administering said GnRH antagonist to said patient in an amount
sufficient to reduce an Endometriosis Health Profile-5 (EHP-5)
score determined for said patient, preferably within about 4 to
about 36 weeks of said administering.
21. The method of claim 20, wherein said EHP-5 score is reduced by
from about 1% to about 50%.
22. The method of any one of claims 1-21, said method comprising
administering said GnRH antagonist to said patient in an amount
that does not cause a reduction in bone mineral density (BMD) in
said patient of greater than 5%.
23. The method of claim 22, said method comprising administering
said GnRH antagonist to said patient in an amount that does not
cause a reduction in BMD in said patient of greater than 1%.
24. The method of any one of claims 1-23, said method comprising
administering add-back therapy to said patient.
25. The method of claim 24, wherein said add-back therapy is
administered to said patient concurrently with said GnRH
antagonist.
26. The method of claim 24, wherein said add-back therapy is
administered to said patient prior to administration of said GnRH
antagonist.
27. The method of claim 24, wherein said add-back therapy is
administered to said patient following administration of said GnRH
antagonist.
28. The method of claim 25, wherein said add-back therapy is
administered to said patient in the form of a pharmaceutical
composition comprising said GnRH antagonist.
29. The method of any one of claims 24-28, wherein said add-back
therapy comprises an estrogen.
30. The method of claim 29, wherein said estrogen is
.beta.17-estradiol.
31. The method of any one of claims 24-30, wherein said add-back
therapy comprises a progestin.
32. The method of claim 31, wherein said progestin is selected from
the group consisting of norethindrone and an ester thereof.
33. The method of claim 32, wherein said progestin is norethindrone
acetate.
34. The method of any one of claims 24-33, wherein said patient
does not exhibit a reduction in BMD of greater than 5% following
administration of said GnRH antagonist and said add-back
therapy.
35. The method of claim 34, wherein said patient does not exhibit a
reduction in BMD of greater than 1% following administration of
said GnRH antagonist and said add-back therapy.
36. The method of any one of claims 22, 23, 34, and 35, wherein
said BMD is assessed by dual energy X-ray absorptiometry.
37. The method of any one of claims 22, 23, and 34-36, wherein said
BMD is assessed in the spine or femur of said patient.
38. The method of any one of claims 1-37, wherein said GnRH
antagonist is a compound represented by formula (I) ##STR00033##
wherein ring A is a thiophene ring; each R.sup.A is independently a
halogen atom, a cyano group, a nitro group, an optionally
substituted lower alkyl group, an optionally substituted lower
alkenyl group, an optionally substituted lower alkynyl group, a
hydroxyiminomethyl group, an optionally substituted sulfonyl group,
an optionally substituted sulfinyl group, a tetrazolyl group,
OW.sup.1, SW.sup.1, COW', COOW.sup.1, NHCOW.sup.1,
NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or
SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently
are a hydrogen atom or an optionally substituted lower alkyl group,
or W.sup.2 and W.sup.3 may bind together with the neighboring
nitrogen atom to form an optionally substituted cyclic amino group;
m is an integer from 0 to 3; ring B is an aryl group or a
monocyclic heteroaryl group; each R.sup.B is independently a
halogen atom, a cyano group, an optionally substituted lower alkyl
group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6,
wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an
optionally substituted lower alkyl group, or W.sup.5 and W.sup.6
may bind together with the neighboring nitrogen atom to form an
optionally substituted cyclic amino group; n is an integer from 0
to 2; U is a single bond; X is a group represented by --S-L-Y,
--O-L-Y, --CO-L-Y, or --SO.sub.2-L-Y, wherein L is an optionally
substituted lower alkylene group; Y is a group represented by Z or
--NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a
hydrogen atom, an optionally substituted lower alkyl group, or Z
with the proviso that W.sup.7 and W.sup.8 are not simultaneously
hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the
neighboring nitrogen atom to form an optionally substituted cyclic
amino group; Z is an optionally fused and optionally substituted
cycloalkyl group, an optionally fused and optionally substituted
heterocycloalkyl group, an optionally fused and optionally
substituted aryl group, or an optionally fused and optionally
substituted heteroaryl group; or a pharmaceutically acceptable salt
thereof.
39. The method of claim 38, wherein said compound is represented by
formula (II) ##STR00034## or a pharmaceutically acceptable salt
thereof.
40. The method of claim 39, wherein said compound is the choline
salt of the compound represented by formula (II).
41. The method of any one of claims 38-40, said method comprising
administering from 85 to 115 mg/day or from 185 to 215 mg/day of
said GnRH antagonist to said patient if the concentration of AMH in
the sample isolated from said patient is above the AMH reference
range.
42. The method of claim 41, said method comprising administering
100 mg/day or 200 mg/day of said GnRH antagonist to said patient if
the concentration of AMH in the sample isolated from said patient
is above the AMH reference range.
43. The method of any one of claims 38-42, said method comprising
administering from 35 to 65 mg/day of said GnRH antagonist to said
patient if the concentration of AMH in the sample isolated from
said patient is below the AMH reference range.
44. The method of claim 43, said method comprising administering 50
mg/day of said GnRH antagonist to said patient if the concentration
of AMH in the sample isolated from said patient is below the AMH
reference range.
45. The method of any one of claims 38-44, said method comprising
administering from 60 to 90 mg/day or from 85 to 115 mg/day of said
GnRH antagonist to said patient if the concentration of AMH in the
sample isolated from said patient is within the AMH reference
range.
46. The method of claim 45, said method comprising administering 75
mg/day or 100 mg/day of said GnRH antagonist to said patient if the
concentration of AMH in the sample isolated from said patient is
within the AMH reference range.
47. The method of any one of claims 1-37, wherein said GnRH
antagonist is selected from the group consisting of elagolix,
relugolix, ASP-1707, SK12670, and BAY-784, or a derivative or
variant thereof.
48. The method of claim 47, wherein said GnRH antagonist is
elagolix.
49. The method of claim 48, said method comprising administering
150 mg/day or more of said GnRH antagonist to said patient if the
concentration of AMH in the sample isolated from said patient is
above the AMH reference range.
50. The method of claim 48, said method comprising administering
400 mg/day or more of said GnRH antagonist to said patient if the
concentration of AMH in the sample isolated from said patient is
above the AMH reference range.
51. The method of any one of claims 48-50, said method comprising
administering 150 mg/day or less of said GnRH antagonist to said
patient if the concentration of AMH in the sample isolated from
said patient is below the AMH reference range.
52. The method of any one of claims 48-50, said method comprising
administering 400 mg/day or less of said GnRH antagonist to said
patient if the concentration of AMH in the sample isolated from
said patient is below the AMH reference range.
53. The method of any one of claims 48-52, said method comprising
administering 150 mg/day of said GnRH antagonist to said patient if
the concentration of AMH in the sample isolated from said patient
is within the AMH reference range.
54. The method of any one of claims 48-52, said method comprising
administering 400 mg/day of said GnRH antagonist to said patient if
the concentration of AMH in the sample isolated from said patient
is within the AMH reference range.
55. The method of claim 47, wherein said GnRH antagonist is
relugolix.
56. The method of claim 55, said method comprising administering 40
mg/day or more of said GnRH antagonist to said patient if the
concentration of AMH in the sample isolated from said patient is
above the AMH reference range.
57. The method of claim 55 or 56, said method comprising
administering 40 mg/day or less of said GnRH antagonist to said
patient if the concentration of AMH in the sample isolated from
said patient is below the AMH reference range.
58. The method of any one of claims 55-57, said method comprising
administering 40 mg/day of said GnRH antagonist to said patient if
the concentration of AMH in the sample isolated from said patient
is within the AMH reference range.
59. The method of claim 47, wherein said GnRH antagonist is
ASP-1707.
60. The method of claim 59, said method comprising administering 10
mg/day or more of said GnRH antagonist to said patient if the
concentration of AMH in the sample isolated from said patient is
above the AMH reference range.
61. The method of claim 59 or 60, said method comprising
administering 10 mg/day or less of said GnRH antagonist to said
patient if the concentration of AMH in the sample isolated from
said patient is below the AMH reference range.
62. The method of any one of claims 59-61, said method comprising
administering 10 mg/day of said GnRH antagonist to said patient if
the concentration of AMH in the sample isolated from said patient
is within the AMH reference range.
63. The method of any one of claims 1-62, said method comprising
orally administering said GnRH antagonist to said patient.
64. The method of any one of claims 1-62, said method comprising
intravenously administering said GnRH antagonist to said
patient.
65. A kit comprising one or more agents capable of detecting AMH
and a package insert, wherein said package insert instructs a user
of said kit to perform the method of any one of claims 1-64.
66. The kit of claim 65, wherein said kit further comprises one or
more agents capable of detecting a compound selected from the group
consisting of E2, LH, and FSH.
67. The kit of claim 65 or 66, wherein said kit further comprises
said GnRH antagonist.
68. A method of treating endometriosis in a human patient
undergoing therapy with a GnRH antagonist, wherein the
concentration of E2 in a sample isolated from said patient has been
determined, said method comprising: a. comparing said concentration
of E2 to an E2 reference range; and b. administering an increased
dose of said GnRH antagonist to said patient if the concentration
of E2 in the sample isolated from said patient is above the E2
reference range, or administering a decreased dose of said GnRH
antagonist to said patient if the concentration of E2 in the sample
isolated from said patient is below the E2 reference range.
69. The method of claim 68, said method comprising administering
the originally dispensed dose of said GnRH antagonist to said
patient if the concentration of E2 in the sample isolated from said
patient is within the E2 reference range.
70. The method of claim 69, wherein said originally dispensed dose
of said GnRH antagonist is from 10 to 500 mg/day.
71. The method of claim 70, wherein said originally dispensed dose
of said GnRH antagonist is 75 mg/day.
72. A method of optimizing a dosing regimen for the treatment of
endometriosis in a human patient undergoing therapy with a GnRH
antagonist, wherein the concentration of E2 in a sample isolated
from said patient has been determined, said method comprising: a.
comparing said concentration of E2 to an E2 reference range; b.
determining that the patient be administered an increased dose of a
GnRH antagonist if the concentration of E2 in the sample isolated
from said patient is above the E2 reference range, determining that
the patient be administered a decreased dose of a GnRH antagonist
if the concentration of E2 in the sample isolated from said patient
is below the E2 reference range, or determining that the patient be
administered the originally dispensed dose of said GnRH antagonist
if the concentration of E2 in the sample isolated from said patient
is within the E2 reference range; and optionally c. administering
said GnRH antagonist to said patient at the dose determined in
(b).
73. The method of any one of claims 68-72, wherein said sample was
isolated from the patient between about 4 and about 36 weeks
following the start of said GnRH antagonist therapy.
74. The method of claim 73, wherein said sample was isolated from
the patient about 4 weeks following the start of said GnRH
antagonist therapy.
75. The method of claim 73, wherein said sample was isolated from
the patient about 8 weeks following the start of said GnRH
antagonist therapy.
76. The method of claim 73, wherein said sample was isolated from
the patient about 12 weeks following the start of said GnRH
antagonist therapy.
77. The method of claim 73, wherein said sample was isolated from
the patient about 24 weeks following the start of said GnRH
antagonist therapy.
78. The method of any one of claims 68-77, wherein said
administering is performed between about 4 weeks and about 36 weeks
following the start of said GnRH antagonist therapy.
79. The method of claim 78, wherein said administering is performed
about 12 weeks following the start of said GnRH antagonist
therapy.
80. The method of claim 78, wherein said administering is performed
about 24 weeks following the start of said GnRH antagonist
therapy.
81. The method of any one of claims 68-80, wherein said E2
reference range is from 20 to 50 pg/ml.
82. The method of any one of claims 68-81, said method comprising
administering said GnRH antagonist to said patient in an amount
sufficient to reduce the serum concentration of E2 in said patient
to between about 20 and about 50 pg/ml, preferably within about 4
to about 36 weeks of said administering.
83. The method of any one of claims 68-82, said method comprising
administering said GnRH antagonist to said patient in an amount
sufficient to reduce the serum concentration of FSH in said patient
to between about 0.1 and about 10 mIU/ml, preferably within about 4
to about 36 weeks of said administering.
84. The method of any one of claims 68-83, said method comprising
administering said GnRH antagonist to said patient in an amount
sufficient to reduce the serum concentration of LH in said patient
to between about 0.1 and about 10 mIU/ml, preferably within about 4
to about 36 weeks of said administering.
85. The method of any one of claims 68-84, said method comprising
administering said GnRH antagonist to said patient in an amount
sufficient to reduce endometriosis-associated pain in said patient,
preferably within about 4 to about 36 weeks of said
administering.
86. The method of claim 85, wherein said endometriosis-associated
pain is selected from the group consisting of pelvic pain,
dyspareunia, and dyschezia.
87. The method of claim 85 or 86, wherein said
endometriosis-associated pain is assessed by determining a
Numerical Rating Score (NRS) for said patient.
88. The method of claim 87, wherein said NRS is reduced by from
about 1% to about 50%.
89. The method of claim 88, wherein said NRS is reduced by about
30%.
90. The method of claim 85 or 86 wherein said
endometriosis-associated pain is assessed by determining a Verbal
Rating Score (VRS) for said patient.
91. The method of claim 90, wherein said VRS is reduced by from
about 1% to about 50%.
92. The method of claim 91, wherein said VRS is reduced by about
30%.
93. The method of any one of claims 68-92, said method comprising
administering said GnRH antagonist to said patient in an amount
sufficient to alleviate a symptom selected from the group
consisting of dysmenorrhea, non-menstrual pelvic pain, and
dyspareunia, preferably within about 4 to about 36 weeks of said
administering.
94. The method of claim 93, wherein said symptom is assessed by
determining a Biberoglu and Behrman (B&B) scale score for said
patient.
95. The method of claim 94, wherein said B&B scale score is
reduced by from about 1% to about 50%.
96. The method of any one of claims 68-95, said method comprising
administering said GnRH antagonist to said patient in an amount
sufficient to reduce an Endometriosis Health Profile-5 (EHP-5)
score determined for said patient, preferably within about 4 to
about 36 weeks of said administering.
97. The method of claim 96, wherein said EHP-5 score is reduced by
from about 1% to about 50%.
98. The method of any one of claims 68-97, said method comprising
administering said GnRH antagonist to said patient in an amount
that does not cause a reduction in BMD in said patient of greater
than 5%.
99. The method of claim 98, said method comprising administering
said GnRH antagonist to said patient in an amount that does not
cause a reduction in BMD in said patient of greater than 1%.
100. The method of any one of claims 68-99, said method comprising
administering add-back therapy to said patient.
101. The method of claim 100, wherein said add-back therapy is
administered to said patient concurrently with said GnRH
antagonist.
102. The method of claim 100, wherein said add-back therapy is
administered to said patient prior to administration of said GnRH
antagonist.
103. The method of claim 100, wherein said add-back therapy is
administered to said patient following administration of said GnRH
antagonist.
104. The method of claim 101, wherein said add-back therapy is
administered to said patient in the form of a pharmaceutical
composition comprising said GnRH antagonist.
105. The method of any one of claims 68-104, wherein said add-back
therapy comprises an estrogen.
106. The method of claim 105, wherein said estrogen is
.beta.17-estradiol.
107. The method of any one of claims 100-106, wherein said add-back
therapy comprises a progestin.
108. The method of claim 107, wherein said progestin is selected
from the group consisting of norethindrone and an ester
thereof.
109. The method of claim 108, wherein said progestin is
norethindrone acetate.
110. The method of any one of claims 100-109, wherein said patient
does not exhibit a reduction in BMD of greater than 5% following
administration of said GnRH antagonist and said add-back
therapy.
111. The method of claim 110, wherein said patient does not exhibit
a reduction in BMD of greater than 1% following administration of
said GnRH antagonist and said add-back therapy.
112. The method of claim any one of claims 98, 99, 110, and 111,
wherein said BMD is assessed by dual energy X-ray
absorptiometry.
113. The method of any one of claims 98, 99, and 110-112, wherein
said BMD is assessed in the spine or femur of said patient.
114. The method of any one of claims 68-113, wherein said GnRH
antagonist is a compound represented by formula (I) ##STR00035##
wherein ring A is a thiophene ring; each R.sup.A is independently a
halogen atom, a cyano group, a nitro group, an optionally
substituted lower alkyl group, an optionally substituted lower
alkenyl group, an optionally substituted lower alkynyl group, a
hydroxyiminomethyl group, an optionally substituted sulfonyl group,
an optionally substituted sulfinyl group, a tetrazolyl group,
OW.sup.1, SW.sup.1, COW', COOW.sup.1, NHCOW.sup.1,
NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or
SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently
are a hydrogen atom or an optionally substituted lower alkyl group,
or W.sup.2 and W.sup.3 may bind together with the neighboring
nitrogen atom to form an optionally substituted cyclic amino group;
m is an integer from 0 to 3; ring B is an aryl group or a
monocyclic heteroaryl group; each R.sup.B is independently a
halogen atom, a cyano group, an optionally substituted lower alkyl
group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6,
wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an
optionally substituted lower alkyl group, or W.sup.5 and W.sup.6
may bind together with the neighboring nitrogen atom to form an
optionally substituted cyclic amino group; n is an integer from 0
to 2; U is a single bond; X is a group represented by --S-L-Y,
--O-L-Y, --CO-L-Y, or --SO.sub.2-L-Y, wherein L is an optionally
substituted lower alkylene group; Y is a group represented by Z or
--NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a
hydrogen atom, an optionally substituted lower alkyl group, or Z
with the proviso that W.sup.7 and W.sup.8 are not simultaneously
hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the
neighboring nitrogen atom to form an optionally substituted cyclic
amino group; Z is an optionally fused and optionally substituted
cycloalkyl group, an optionally fused and optionally substituted
heterocycloalkyl group, an optionally fused and optionally
substituted aryl group, or an optionally fused and optionally
substituted heteroaryl group; or a pharmaceutically acceptable salt
thereof.
115. The method of claim 114, wherein said compound is represented
by formula (II) ##STR00036## or a pharmaceutically acceptable salt
thereof.
116. The method of claim 115, wherein said compound is the choline
salt of the compound represented by formula (II).
117. The method of any one of claims 114-116, said method
comprising administering from 85 to 115 mg/day or from 185 to 215
mg/day of said GnRH antagonist to said patient if the concentration
of E2 in the sample isolated from said patient is above the E2
reference range.
118. The method of claim 117, said method comprising administering
100 mg/day or 200 mg/day of said GnRH antagonist to said patient if
the concentration of E2 in the sample isolated from said patient is
above the E2 reference range.
119. The method of any one of claims 114-118, said method
comprising administering from 35 to 65 mg/day of said GnRH
antagonist to said patient if the concentration of E2 in the sample
isolated from said patient is below the E2 reference range.
120. The method of claim 119, said method comprising administering
50 mg/day of said GnRH antagonist to said patient if the
concentration of E2 in the sample isolated from said patient is
below the E2 reference range.
121. The method of any one of claims 114-120, said method
comprising administering from 60 to 90 mg/day or from 85 to 115
mg/day of said GnRH antagonist to said patient if the concentration
of E2 in the sample isolated from said patient is within the E2
reference range.
122. The method of claim 121, said method comprising administering
75 mg/day or 100 mg/day of said GnRH antagonist to said patient if
the concentration of E2 in the sample isolated from said patient is
within the E2 reference range.
123. The method of any one of claims 68-113, wherein said GnRH
antagonist is selected from the group consisting of elagolix,
relugolix, ASP-1707, SK12670, and BAY-784.
124. The method of claim 123, wherein said GnRH antagonist is
elagolix.
125. The method of claim 124, said method comprising administering
150 mg/day or more of said GnRH antagonist to said patient if the
concentration of E2 in the sample isolated from said patient is
above the E2 reference range.
126. The method of claim 124, said method comprising administering
400 mg/day or more of said GnRH antagonist to said patient if the
concentration of E2 in the sample isolated from said patient is
above the E2 reference range.
127. The method of any one of claims 124-126, said method
comprising administering 150 mg/day or less of said GnRH antagonist
to said patient if the concentration of E2 in the sample isolated
from said patient is below the E2 reference range.
128. The method of any one of claims 124-126, said method
comprising administering 400 mg/day or less of said GnRH antagonist
to said patient if the concentration of E2 in the sample isolated
from said patient is below the E2 reference range.
129. The method of any one of claims 124-128, said method
comprising administering 150 mg/day of said GnRH antagonist to said
patient if the concentration of E2 in the sample isolated from said
patient is within the E2 reference range.
130. The method of any one of claims 124-128, said method
comprising administering 400 mg/day of said GnRH antagonist to said
patient if the concentration of E2 in the sample isolated from said
patient is within the E2 reference range.
131. The method of claim 123, wherein said GnRH antagonist is
relugolix.
132. The method of claim 131, said method comprising administering
40 mg/day or more of said GnRH antagonist to said patient if the
concentration of E2 in the sample isolated from said patient is
above the E2 reference range.
133. The method of claim 131 or 132, said method comprising
administering 40 mg/day or less of said GnRH antagonist to said
patient if the concentration of E2 in the sample isolated from said
patient is below the E2 reference range.
134. The method of any one of claims 131-133, said method
comprising administering 40 mg/day of said GnRH antagonist to said
patient if the concentration of E2 in the sample isolated from said
patient is within the E2 reference range.
135. The method of claim 123, wherein said GnRH antagonist is
ASP-1707.
136. The method of claim 135, said method comprising administering
10 mg/day or more of said GnRH antagonist to said patient if the
concentration of E2 in the sample isolated from said patient is
above the E2 reference range.
137. The method of claim 135 or 136, said method comprising
administering 10 mg/day or less of said GnRH antagonist to said
patient if the concentration of E2 in the sample isolated from said
patient is below the E2 reference range.
138. The method of any one of claims 135-137, said method
comprising administering 10 mg/day of said GnRH antagonist to said
patient if the concentration of E2 in the sample isolated from said
patient is within the E2 reference range.
139. The method of any one of claims 68-138, said method comprising
orally administering said GnRH antagonist to said patient.
140. The method of any one of claims 68-138, said method comprising
intravenously administering said GnRH antagonist to said
patient.
141. A kit comprising one or more agents capable of detecting E2
and a package insert, wherein said package insert instructs a user
of said kit to perform the method of any one of claims 68-140.
142. The kit of claim 141, wherein said kit further comprises one
or more agents capable of detecting a compound selected from the
group consisting of LH and FSH.
143. The kit of claim 141 or 142, wherein said kit further
comprises said GnRH antagonist.
144. A method of treating endometriosis in a human patient, said
method comprising administering to said patient a compound
represented by formula (II), ##STR00037## or a pharmaceutically
acceptable salt thereof, optionally wherein the compound is choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate, in an
amount of from about 50 mg/day to about 200 mg/day.
145. A method of reducing the concentration of E2,
follicle-stimulating hormone (FSH), and/or luteinizing hormone (LH)
in the blood of a human patient, said method comprising
administering to said patient a compound represented by formula
(II), ##STR00038## or a pharmaceutically acceptable salt thereof,
optionally wherein the compound is choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate, in an
amount of from about 50 mg/day to about 200 mg/day.
146. A method of reducing endometriosis-associated pain in a human
patient in need thereof, said method comprising administering to
said patient a compound represented by formula (II), ##STR00039##
or a pharmaceutically acceptable salt thereof, optionally wherein
the compound is choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate, in an
amount of from about 50 mg/day to about 200 mg/day.
147. The method of any one of claims 144-146, wherein said compound
is administered to said patient in an amount of about 50
mg/day.
148. The method of any one of claims 144-146, wherein said compound
is administered to said patient in an amount of about 75
mg/day.
149. The method of any one of claims 144-146, wherein said compound
is administered to said patient in an amount of about 100
mg/day.
150. The method of any one of claims 144-146, wherein said compound
is administered to said patient in an amount of about 200
mg/day.
151. The method of any one of claims 144-150, wherein said compound
is choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate and
is in a crystalline state.
152. The method of claim 151, wherein said compound exhibits
characteristic X-ray powder diffraction peaks at about 7.1.degree.
2.theta., about 11.5.degree. 2.theta., about 19.4.degree. 2.theta.,
about 21.5.degree. 2.theta., about 22.0.degree. 2.theta., about
22.6.degree. 2.theta., about 23.5.degree. 2.theta., and about
26.2.degree. 20.
153. The method of claim 151 or 152, wherein said compound exhibits
.sup.13C solid-state NMR peaks centered at about 55.5 ppm, about
57.1 ppm, about 58.7 ppm, about 69.8 ppm, about 98.1 ppm, about
110.3 ppm, about 111.6 ppm, about 113.7 ppm, about 118.0 ppm, about
145.3 ppm, about 149.8 ppm, and about 155.8 ppm.
154. The method of any one of claims 151-153, wherein said compound
salt exhibits .sup.19F solid-state NMR peaks centered at about
-151.8 ppm, -145.2 ppm, and -131.6 ppm.
155. The method of any one of claims 144-154, wherein said compound
is orally administered to said patient.
156. The method of any one of claims 144-155, said method
comprising administering add-back therapy to said patient.
157. The method of claim 156, wherein said add-back therapy is
administered to said patient one or more times daily.
158. The method of claim 157, wherein said add-back therapy is
administered to said patient once daily, concurrently with said
compound.
159. The method of claim 157, wherein said add-back therapy is
administered to said patient once daily, prior to administration of
said compound.
160. The method of claim 157, wherein said add-back therapy is
administered to said patient once daily, following administration
of said compound.
161. The method of claim 158, wherein said add-back therapy is
administered to said patient in the form of a pharmaceutical
composition comprising said compound.
162. The method of any one of claims 156-161, wherein said add-back
therapy comprises an estrogen.
163. The method of claim 162, wherein said estrogen is selected
from the group consisting of 617-estradiol, ethinyl estradiol, and
conjugated estrogens.
164. The method of claim 163, wherein said estrogen is
.beta.17-estradiol.
165. The method of claim 164, wherein said .beta.17-estradiol is
administered to said patient at a dose of about 1.0 mg/day.
166. The method of claim 164, wherein said .beta.17-estradiol is
administered to said patient at a dose of about 0.5 mg/day.
167. The method of claim 163, wherein said estrogen is ethinyl
estradiol.
168. The method of claim 167, wherein said ethinyl estradiol is
administered to said patient at a dose of about 5.0 pg/day.
169. The method of claim 167, wherein said ethinyl estradiol is
administered to said patient at a dose of about 2.5 pg/day.
170. The method of claim 163, wherein said estrogen is a conjugated
estrogen.
171. The method of claim 170, wherein said conjugated estrogen is
administered to said patient at a dose of about 0.625 mg/day.
172. The method of claim 170, wherein said conjugated estrogen is
administered to said patient at a dose of about 0.45 mg/day.
173. The method of claim 170, wherein said conjugated estrogen is
administered to said patient at a dose of about 0.3 mg/day
174. The method of any one of claims 156-173, wherein said add-back
therapy comprises a progestin.
175. The method of claim 174, wherein said progestin is selected
from the group consisting of norethindrone or an ester thereof,
progesterone, norgestimate, medroxyprogesterone, and
drospirenone.
176. The method of claim 175, wherein said progestin is
norethindrone or norethindrone acetate.
177. The method of claim 176, wherein said norethindrone or
norethindrone acetate is administered to said patient at a dose of
about 1.0 mg/day.
178. The method of claim 176, wherein said norethindrone or
norethindrone acetate is administered to said patient at a dose of
about 0.5 mg/day.
179. The method of claim 176, wherein said norethindrone or
norethindrone acetate is administered to said patient at a dose of
about 0.1 mg/day.
180. The method of claim 175, wherein said progestin is
progesterone.
181. The method of claim 180, wherein said progesterone is
administered to said patient ata dose of about 200 mg/day.
182. The method of claim 180, wherein said progesterone is
administered to said patient at a dose of about 100 mg/day.
183. The method of claim 175, wherein said progestin is
norgestimate.
184. The method of claim 183, wherein said norgestimate is
administered to said patient at a dose of about 0.09 mg/day.
185. The method of claim 175, wherein said progestin is
medroxyprogesterone.
186. The method of claim 185, wherein said medroxyprogesterone is
administered to said patient at a dose of about 5 mg/day.
187. The method of claim 185, wherein said medroxyprogesterone is
administered to said patient at a dose of about 2.5 mg/day.
188. The method of claim 185, wherein said medroxyprogesterone is
administered to said patient at a dose of about 1.5 mg/day.
189. The method of claim 175, wherein said progestin is
drospirenone.
190. The method of claim 189, wherein said drospirenone is
administered to said patient at a dose of about 0.5 mg/day.
191. The method of claim 189, wherein said drospirenone is
administered to said patient ata dose of about 0.25 mg/day.
192. The method of any one of claims 156-161, wherein said add-back
therapy comprises about 1.0 mg of .beta.17-estradiol and about 0.5
mg of norethindrone acetate.
193. The method of any one of claims 156-161, wherein said add-back
therapy comprises about 0.5 mg of .beta.17-estradiol and about 0.1
mg of norethindrone acetate.
194. The method of any one of claims 144-193, wherein said patient
exhibits reduced pelvic pain following administration of said
compound to said patient.
195. The method of any one of claims 144-194, wherein said patient
exhibits reduced back pain following administration of said
compound to said patient.
196. The method of any one of claims 144-195, wherein said patient
does not exhibit a reduction in BMD of greater than 5% following
administration of said compound to said patient.
197. The method of claim 196, wherein said patient does not exhibit
a reduction in BMD of greater than 1% following administration of
said compound to said patient.
198. The method of claim 196 or 197, wherein said BMD is assessed
by dual energy X-ray absorptiometry.
199. A kit comprising a compound represented by formula (II),
##STR00040## or a pharmaceutically acceptable salt thereof,
optionally wherein the compound is choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate, and a
package insert instructing a user of said kit to perform the method
of any one of claims 144-198.
200. The kit of claim 199, wherein the compound is choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate.
Description
FIELD OF THE INVENTION
[0001] The invention relates to methods of determining dosing
regimens for gonadotropin-releasing hormone antagonists for the
treatment of endometriosis.
BACKGROUND OF THE INVENTION
[0002] Endometriosis is an estrogen-dependent gynecological
condition, characterized by the presence of endometrial-like tissue
outside the uterus, and is one of the most common sex
hormone-dependent diseases. The condition is predominantly observed
in women in their reproductive years and disappears spontaneously
after menopause. A chronic inflammatory reaction induced by the
ectopic endometrial cells, endometriosis may result in infertility
and a variety of pain symptoms including dysmenorrhea, dyspareunia,
chronic pelvic pain, dysuria, and dyschezia, among others.
[0003] A principal objective in treating endometriosis is achieving
symptomatic relief. Treatment options for women with
endometriosis-associated pain are diverse and include analgesic
therapies, hormonal therapies, conservative or minimal invasive
surgery, or a combination of these treatment options. Hormonal
therapies aim at inhibition of ovulation, prevention of cyclic
endometrium growth, and abolition of menstruation through
achievement of a stable steroid hormone milieu. These strategies
are predicated on the concept that the response of the eutopic and
ectopic endometrium to steroid hormones is substantially
similar.
[0004] Combined oral contraceptives (COCs), although not currently
approved for the treatment of endometriosis-associated pain, are
often used as initial therapy. Their intake results in anovulation,
reduction of menstrual blood flow, decidualization of endometriotic
lesions, attenuation of cell proliferation, and enhanced apoptosis
in the endometrium. However, over time many women taking COCs no
longer experience adequate pain relief and often require
second-line therapy.
[0005] Progestin monotherapy can be efficacious for the reduction
in endometriosis-associated pain as it induces anovulation and a
hypoestrogenic state via suppression of pituitary gonadotropin
release. Progestins also exert direct effects on the endometrium,
causing decidualization of eutopic and ectopic endometrium leading
to atrophy of the endometriotic implants. However, progestin
monotherapy is often associated with breakthrough bleeding,
alterations in mood, weight gain, and breast tenderness.
[0006] Other therapies with proven efficacy for the treatment of
endometriosis-associated pain are often limited by undesirable side
effects. For example, GnRH agonists induce a constant stimulation
of the GnRH receptor at the pituitary level, thus desensitizing
this receptor and ultimately causing suppression of ovulation and
reduced serum estrogen levels. The use of GnRH receptor agonists is
thus associated with significant hypoestrogenic side effects.
Short-term effects include menopausal symptoms such as hot flashes,
vaginal dryness, loss of libido, and emotional lability, and their
long-term use is limited by substantial bone mineral density (BMD)
reduction.
[0007] GnRH antagonists represent a therapeutic modality for the
treatment of endometriosis that enables dose-dependent control of
.beta.17-estradiol (E2) levels. There remains a need for improved
GnRH antagonist dosing regimens capable of reducing endometriosis
implants and endometriosis-associated pain without inducing
hypo-estrogenic side effects, such as hot flashes and BMD loss, as
well as methods of determining such dosing schedules on the basis
of the concentration of one or more endogenous hormones in a
patient.
SUMMARY OF THE INVENTION
[0008] The invention provides compositions and methods for dosing a
patient with a gonadotropin-releasing hormone (GnRH) receptor
antagonist for the treatment of endometriosis based on the level of
one or more endogenous substances within the patient. In some
embodiments of the invention, GnRH antagonist dosing regimens are
determined by analyzing the concentration of anti-Mullerian hormone
(AMH) in a sample isolated from the patient. In some embodiments,
GnRH antagonist dosing regimens are determined by analyzing the
concentration of .beta.17-estradiol (E2) in a sample isolated from
the patient. The GnRH antagonist may be a thieno[3,4d]pyrimidine
derivative or variant, such as
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or the
choline salt thereof. In some embodiments, the GnRH antagonist is
elagolix, relugolix, ASP-1707, SKI2670, BAY-784, or a derivative or
variant thereof, among others.
[0009] In a first aspect, the invention features a method of
treating endometriosis in a patient (e.g., a female human patient,
such as a premenopausal female human patient). In another aspect,
the invention features a method of reducing the concentration of
E2, follicle-stimulating hormone (FSH), and/or luteinizing hormone
(LH) in the blood of a patient (e.g., a female human patient, such
as a premenopausal female human patient). In another aspect, the
invention features a method of reducing pain (e.g.,
endometriosis-associated pain) in a patient (e.g., a female human
patient, such as a premenopausal female human patient).
[0010] In any of the above aspects of the invention, the method may
include the step of determining the concentration of AMH in a
sample (e.g., a blood sample) isolated from the patient. In some
embodiments, the concentration of AMH in a sample (e.g., a blood
sample) isolated from the patient has previously been determined.
The method may include: [0011] a. comparing the concentration of
AMH to an AMH reference range; and [0012] b. administering a higher
quantity (e.g., a higher daily dosage or an elevated dosing
frequency) of a GnRH antagonist to the patient if the concentration
of AMH in the sample isolated from the patient is above the AMH
reference range; [0013] c. administering a lower quantity (e.g., a
lower daily dosage or a reduced dosing frequency) of a GnRH
antagonist to the patient if the concentration of AMH in the sample
isolated from the patient is below the AMH reference range; or
[0014] d. administering an intermediate quantity (e.g.,
intermediate daily dosage or intermediate dosing frequency) of a
GnRH antagonist to the patient if the concentration of AMH in the
sample isolated from the patient is within the AMH reference
range.
[0015] In some embodiments, the method includes determining that
the concentration of AMH in the sample isolated from the patient is
greater than an AMH reference range, and may further include
administering a higher quantity (e.g., a higher daily dosage or an
elevated dosing frequency) of a GnRH antagonist to the patient
accordingly.
[0016] In some embodiments, the method includes determining that
the concentration of AMH in the sample isolated from the patient is
less than an AMH reference range, and may further include
administering a lower quantity (e.g., a lower daily dosage or a
reduced dosing frequency) of a GnRH antagonist to the patient
accordingly.
[0017] In some embodiments, the method includes determining that
the concentration of AMH in the sample isolated from the patient is
within an AMH reference range, and may further include
administering an intermediate quantity (e.g., an intermediate daily
dosage or an intermediate dosing frequency) of a GnRH antagonist to
the patient accordingly.
[0018] In some embodiments, the method includes administering from
5 to 700 mg/day of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range.
[0019] For instance, in some embodiments, the method includes
administering from 10 to 600 mg/day, from 20 to 590 mg/day, from 30
to 580 mg/day, from 40 to 570 mg/day, from 50 to 560 mg/day, from
60 to 550 mg/day, from 70 to 540 mg/day, from 80 to 530 mg/day,
from 90 to 520 mg/day, from 100 to 510 mg/day, or from 110 to 500
mg/day (e.g., 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, 25 mg/day,
30 mg/day, 35 mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day,
60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day,
90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110 mg/day, 115
mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day,
145 mg/day, 150 mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170
mg/day, 175 mg/day, 180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day,
200 mg/day, 205 mg/day, 210 mg/day, 215 mg/day, 220 mg/day, 225
mg/day, 230 mg/day, 235 mg/day, 240 mg/day, 245 mg/day, 250 mg/day,
255 mg/day, 260 mg/day, 265 mg/day, 270 mg/day, 275 mg/day, 280
mg/day, 285 mg/day, 290 mg/day, 295 mg/day, 300 mg/day, 305 mg/day,
310 mg/day, 315 mg/day, 320 mg/day, 325 mg/day, 330 mg/day, 335
mg/day, 340 mg/day, 345 mg/day, 350 mg/day, 355 mg/day, 360 mg/day,
365 mg/day, 370 mg/day, 375 mg/day, 380 mg/day, 385 mg/day, 390
mg/day, 395 mg/day, 400 mg/day, 405 mg/day, 410 mg/day, 415 mg/day,
420 mg/day, 425 mg/day, 430 mg/day, 435 mg/day, 440 mg/day, 445
mg/day, 450 mg/day, 455 mg/day, 460 mg/day, 465 mg/day, 470 mg/day,
475 mg/day, 480 mg/day, 485 mg/day, 490 mg/day, 495 mg/day, 500
mg/day, 505 mg/day, 510 mg/day, 515 mg/day, 520 mg/day, 525 mg/day,
530 mg/day, 535 mg/day, 540 mg/day, 545 mg/day, 550 mg/day, 555
mg/day, 560 mg/day, 565 mg/day, 570 mg/day, 575 mg/day, 580 mg/day,
585 mg/day, 590 mg/day, 595 mg/day, 600 mg/day, 605 mg/day, 610
mg/day, 615 mg/day, 620 mg/day, 625 mg/day, 630 mg/day, 635 mg/day,
640 mg/day, 645 mg/day, 650 mg/day, 655 mg/day, 660 mg/day, 665
mg/day, 670 mg/day, 675 mg/day, 680 mg/day, 685 mg/day, 690 mg/day,
695 mg/day, or 700 mg/day) of a GnRH antagonist to the patient if
the concentration of AMH in the sample isolated from the patient is
above the AMH reference range.
[0020] In some embodiments, the method includes administering more
than 10 mg/day of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range. For instance, the method may include
administering more than 10 mg/day of ASP-1707 to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range.
[0021] In some embodiments, the method includes administering more
than 40 mg/day of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range. For instance, the method may include
administering more than 40 mg/day of relugolix to the patient if
the concentration of AMH in the sample isolated from the patient is
above the AMH reference range.
[0022] In some embodiments, the method includes administering from
75 mg/day to 200 mg/day of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range. For instance, the method may include
administering 75 mg/day, 100 mg/day, or 200 mg/day of a
thieno[3,4d]pyrimidine derivative or variant, such as
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or the
choline salt thereof to the patient if the concentration of AMH in
the sample isolated from the patient is above the AMH reference
range.
[0023] In some embodiments, the method includes administering more
than 150 mg/day of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range. For instance, the method may include
administering more than 150 mg/day of elagolix to the patient if
the concentration of AMH in the sample isolated from the patient is
above the AMH reference range. In some embodiments, the method
includes administering more than 400 mg/day of a GnRH antagonist to
the patient if the concentration of AMH in the sample isolated from
the patient is above the AMH reference range. For instance, the
method may include administering more than 400 mg/day of elagolix
to the patient if the concentration of AMH in the sample isolated
from the patient is above the AMH reference range.
[0024] In some embodiments, the method includes administering from
5 to 400 mg/day of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range.
[0025] For instance, in some embodiments, the method includes
administering from 5 to 190 mg/day, from 15 to 180 mg/day, from 35
to 170 mg/day, from 50 to 160 mg/day, from 60 to 150 mg/day, from
70 to 140 mg/day, from 80 to 130 mg/day, from 90 to 120 mg/day,
from 100 to 110 mg/day, from 200 to 400 mg/day, from 225 to 375
mg/day, from 250 to 350 mg/day, or from 275 to 325 mg/day (e.g., 5
mg/day, 10 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35
mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65
mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95
mg/day, 100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120 mg/day,
125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150
mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day,
180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day, 200 mg/day, 205
mg/day, 210 mg/day, 215 mg/day, 220 mg/day, 225 mg/day, 230 mg/day,
235 mg/day, 240 mg/day, 245 mg/day, 250 mg/day, 255 mg/day, 260
mg/day, 265 mg/day, 270 mg/day, 275 mg/day, 280 mg/day, 285 mg/day,
290 mg/day, 295 mg/day, 300 mg/day, 305 mg/day, 310 mg/day, 315
mg/day, 320 mg/day, 325 mg/day, 330 mg/day, 335 mg/day, 340 mg/day,
345 mg/day, 350 mg/day, 355 mg/day, 360 mg/day, 365 mg/day, 370
mg/day, 375 mg/day, 380 mg/day, 385 mg/day, 390 mg/day, 395 mg/day,
or 400 mg/day) of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range.
[0026] In some embodiments, the method includes administering less
than 10 mg/day of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range. For instance, the method may include
administering less than 10 mg/day of ASP-1707 to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range.
[0027] In some embodiments, the method includes administering less
than 40 mg/day of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range. For instance, the method may include
administering less than 40 mg/day of relugolix to the patient if
the concentration of AMH in the sample isolated from the patient is
below the AMH reference range.
[0028] In some embodiments, the method includes administering from
50 mg/day to 200 mg/day of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range. For instance, the method may include
administering 50 mg/day, 75 mg/day, 100 mg/day, or 200 mg/day of a
thieno[3,4d]pyrimidine derivative or variant, such as
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or the
choline salt thereof to the patient if the concentration of AMH in
the sample isolated from the patient is below the AMH reference
range.
[0029] In some embodiments, the method includes administering less
than 150 mg/day of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range. For instance, the method may include
administering less than 150 mg/day of elagolix to the patient if
the concentration of AMH in the sample isolated from the patient is
below the AMH reference range. In some embodiments, the method
includes administering less than 400 mg/day of a GnRH antagonist to
the patient if the concentration of AMH in the sample isolated from
the patient is below the AMH reference range. For instance, the
method may include administering less than 400 mg/day of elagolix
to the patient if the concentration of AMH in the sample isolated
from the patient is below the AMH reference range.
[0030] In some embodiments, the method includes administering from
10 to 500 mg/day of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range.
[0031] For instance, in some embodiments, the method includes
administering from 10 to 490 mg/day, from 25 to 480 mg/day, from 50
to 470 mg/day, or from 100 to 450 mg/day (e.g., 10 mg/day, 15
mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 45
mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75
mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105
mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day,
135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, 160
mg/day, 165 mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day,
190 mg/day, 195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, 215
mg/day, 220 mg/day, 225 mg/day, 230 mg/day, 235 mg/day, 240 mg/day,
245 mg/day, 250 mg/day, 255 mg/day, 260 mg/day, 265 mg/day, 270
mg/day, 275 mg/day, 280 mg/day, 285 mg/day, 290 mg/day, 295 mg/day,
300 mg/day, 305 mg/day, 310 mg/day, 315 mg/day, 320 mg/day, 325
mg/day, 330 mg/day, 335 mg/day, 340 mg/day, 345 mg/day, 350 mg/day,
355 mg/day, 360 mg/day, 365 mg/day, 370 mg/day, 375 mg/day, 380
mg/day, 385 mg/day, 390 mg/day, 395 mg/day, 400 mg/day, 405 mg/day,
410 mg/day, 415 mg/day, 420 mg/day, 425 mg/day, 430 mg/day, 435
mg/day, 440 mg/day, 445 mg/day, 450 mg/day, 455 mg/day, 460 mg/day,
465 mg/day, 470 mg/day, 475 mg/day, 480 mg/day, 485 mg/day, 490
mg/day, 495 mg/day, or 500 mg/day) of a GnRH antagonist to the
patient if the concentration of AMH in the sample isolated from the
patient is within the AMH reference range.
[0032] In some embodiments, the method includes administering 10
mg/day of a GnRH antagonist to the patient if the concentration of
AMH in the sample isolated from the patient is within the AMH
reference range. For instance, the method may include administering
10 mg/day of ASP-1707 to the patient if the concentration of AMH in
the sample isolated from the patient is within the AMH reference
range.
[0033] In some embodiments, the method includes administering 40
mg/day of a GnRH antagonist to the patient if the concentration of
AMH in the sample isolated from the patient is within the AMH
reference range. For instance, the method may include administering
40 mg/day of relugolix to the patient if the concentration of AMH
in the sample isolated from the patient is within the AMH reference
range.
[0034] In some embodiments, the method includes administering from
50 mg/day to 200 mg/day of a GnRH antagonist to the patient if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range. For instance, the method may
include administering 50 mg/day, 75 mg/day, 100 mg/day, or 200
mg/day of a thieno[3,4d]pyrimidine derivative or variant, such as
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or the
choline salt thereof to the patient if the concentration of AMH in
the sample isolated from the patient is within the AMH reference
range.
[0035] In some embodiments, the method includes administering 150
mg/day of a GnRH antagonist to the patient if the concentration of
AMH in the sample isolated from the patient is within the AMH
reference range. For instance, the method may include administering
150 mg/day of elagolix to the patient if the concentration of AMH
in the sample isolated from the patient is within the AMH reference
range. In some embodiments, the method includes administering 400
mg/day of a GnRH antagonist to the patient if the concentration of
AMH in the sample isolated from the patient is within the AMH
reference range. For instance, the method may include administering
400 mg/day of elagolix to the patient if the concentration of AMH
in the sample isolated from the patient is within the AMH reference
range.
[0036] In another aspect, the invention features a method of
determining a dosing regimen for the treatment of endometriosis in
a patient (e.g., a female human patient, such as a premenopausal
female human patient). In another aspect, the invention features a
method of determining a dosing regimen for reducing pain (e.g.,
endometriosis-associated pain) in a patient (e.g., a female human
patient, such as a premenopausal female human patient).
[0037] In any of the above aspects of the invention, the method may
include the step of determining the concentration of AMH in a
sample (e.g., a blood sample) isolated from the patient. In some
embodiments, the concentration of AMH in a sample (e.g., a blood
sample) isolated from the patient has previously been determined.
The method may include: [0038] a. comparing the concentration of
AMH to an AMH reference range; [0039] b. determining that the
patient be administered a higher quantity (e.g., a higher daily
dosage or an elevated dosing frequency) of a GnRH antagonist to the
patient if the concentration of AMH in the sample isolated from the
patient is above the AMH reference range; [0040] c. determining
that the patient be administered a lower quantity (e.g., a lower
daily dosage or a reduced dosing frequency) of a GnRH antagonist to
the patient if the concentration of AMH in the sample isolated from
the patient is below the AMH reference range; or [0041] d.
determining that the patient be administered an intermediate
quantity (e.g., intermediate daily dosage or intermediate dosing
frequency) of a GnRH antagonist to the patient if the concentration
of AMH in the sample isolated from the patient is within the AMH
reference range.
[0042] In some embodiments, the method includes administering the
GnRH antagonist to the patient at the determined dose.
[0043] For instance, in some embodiments, the method includes
determining that the patient be administered from 10 to 600 mg/day,
from 20 to 590 mg/day, from 30 to 580 mg/day, from 40 to 570
mg/day, from 50 to 560 mg/day, from 60 to 550 mg/day, from 70 to
540 mg/day, from 80 to 530 mg/day, from 90 to 520 mg/day, from 100
to 510 mg/day, or from 110 to 500 mg/day (e.g., 5 mg/day, 10
mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40
mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70
mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100
mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125 mg/day,
130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day, 155
mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day, 180 mg/day,
185 mg/day, 190 mg/day, 195 mg/day, 200 mg/day, 205 mg/day, 210
mg/day, 215 mg/day, 220 mg/day, 225 mg/day, 230 mg/day, 235 mg/day,
240 mg/day, 245 mg/day, 250 mg/day, 255 mg/day, 260 mg/day, 265
mg/day, 270 mg/day, 275 mg/day, 280 mg/day, 285 mg/day, 290 mg/day,
295 mg/day, 300 mg/day, 305 mg/day, 310 mg/day, 315 mg/day, 320
mg/day, 325 mg/day, 330 mg/day, 335 mg/day, 340 mg/day, 345 mg/day,
350 mg/day, 355 mg/day, 360 mg/day, 365 mg/day, 370 mg/day, 375
mg/day, 380 mg/day, 385 mg/day, 390 mg/day, 395 mg/day, 400 mg/day,
405 mg/day, 410 mg/day, 415 mg/day, 420 mg/day, 425 mg/day, 430
mg/day, 435 mg/day, 440 mg/day, 445 mg/day, 450 mg/day, 455 mg/day,
460 mg/day, 465 mg/day, 470 mg/day, 475 mg/day, 480 mg/day, 485
mg/day, 490 mg/day, 495 mg/day, 500 mg/day, 505 mg/day, 510 mg/day,
515 mg/day, 520 mg/day, 525 mg/day, 530 mg/day, 535 mg/day, 540
mg/day, 545 mg/day, 550 mg/day, 555 mg/day, 560 mg/day, 565 mg/day,
570 mg/day, 575 mg/day, 580 mg/day, 585 mg/day, 590 mg/day, 595
mg/day, 600 mg/day, 605 mg/day, 610 mg/day, 615 mg/day, 620 mg/day,
625 mg/day, 630 mg/day, 635 mg/day, 640 mg/day, 645 mg/day, 650
mg/day, 655 mg/day, 660 mg/day, 665 mg/day, 670 mg/day, 675 mg/day,
680 mg/day, 685 mg/day, 690 mg/day, 695 mg/day, or 700 mg/day) of a
GnRH antagonist if the concentration of AMH in the sample isolated
from the patient is above the AMH reference range.
[0044] In some embodiments, the method includes determining that
the patient be administered more than 10 mg/day of a GnRH
antagonist if the concentration of AMH in the sample isolated from
the patient is above the AMH reference range. For instance, the
method may include determining that the patient be administered
more than 10 mg/day of ASP-1707 if the concentration of AMH in the
sample isolated from the patient is above the AMH reference
range.
[0045] In some embodiments, the method includes determining that
the patient be administered more than 40 mg/day of a GnRH
antagonist if the concentration of AMH in the sample isolated from
the patient is above the AMH reference range. For instance, the
method may include determining that the patient be administered
more than 40 mg/day of relugolix if the concentration of AMH in the
sample isolated from the patient is above the AMH reference
range.
[0046] In some embodiments, the method includes determining that
the patient be administered from about 50 mg/day to about 200
mg/day of a GnRH antagonist if the concentration of AMH in the
sample isolated from the patient is above the AMH reference range.
For instance, the method may include determining that the patient
be administered about 50 mg/day, 75 mg/day, 100 mg/day, or 200
mg/day of a thieno[3,4d]pyrimidine derivative or variant, such as
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or the
choline salt thereof if the concentration of AMH in the sample
isolated from the patient is above the AMH reference range.
[0047] In some embodiments, the method includes determining that
the patient be administered more than 150 mg/day of a GnRH
antagonist if the concentration of AMH in the sample isolated from
the patient is above the AMH reference range. For instance, the
method may include determining that the patient be administered
more than 150 mg/day of elagolix if the concentration of AMH in the
sample isolated from the patient is above the AMH reference range.
In some embodiments, the method includes determining that the
patient be administered more than 400 mg/day of a GnRH antagonist
if the concentration of AMH in the sample isolated from the patient
is above the AMH reference range. For instance, the method may
include determining that the patient be administered more than 400
mg/day of elagolix if the concentration of AMH in the sample
isolated from the patient is above the AMH reference range.
[0048] In some embodiments, the method includes determining that
the patient be administered from 5 to 400 mg/day of a GnRH
antagonist if the concentration of AMH in the sample isolated from
the patient is below the AMH reference range. For instance, in some
embodiments, the method includes determining that the patient be
administered from 5 to 190 mg/day, from 15 to 180 mg/day, from 35
to 170 mg/day, from 50 to 160 mg/day, from 60 to 150 mg/day, from
70 to 140 mg/day, from 80 to 130 mg/day, from 90 to 120 mg/day,
from 100 to 110 mg/day, from 200 to 400 mg/day, from 225 to 375
mg/day, from 250 to 350 mg/day, or from 275 to 325 mg/day (e.g., 5
mg/day, 10 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35
mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65
mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95
mg/day, 100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120 mg/day,
125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150
mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day,
180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day, 200 mg/day, 205
mg/day, 210 mg/day, 215 mg/day, 220 mg/day, 225 mg/day, 230 mg/day,
235 mg/day, 240 mg/day, 245 mg/day, 250 mg/day, 255 mg/day, 260
mg/day, 265 mg/day, 270 mg/day, 275 mg/day, 280 mg/day, 285 mg/day,
290 mg/day, 295 mg/day, 300 mg/day, 305 mg/day, 310 mg/day, 315
mg/day, 320 mg/day, 325 mg/day, 330 mg/day, 335 mg/day, 340 mg/day,
345 mg/day, 350 mg/day, 355 mg/day, 360 mg/day, 365 mg/day, 370
mg/day, 375 mg/day, 380 mg/day, 385 mg/day, 390 mg/day, 395 mg/day,
or 400 mg/day) of a GnRH antagonist if the concentration of AMH in
the sample isolated from the patient is below the AMH reference
range.
[0049] In some embodiments, the method includes determining that
the patient be administered less than 10 mg/day of a GnRH
antagonist if the concentration of AMH in the sample isolated from
the patient is below the AMH reference range. For instance, the
method may include determining that the patient be administered
less than 10 mg/day of ASP-1707 if the concentration of AMH in the
sample isolated from the patient is below the AMH reference
range.
[0050] In some embodiments, the method includes determining that
the patient be administered less than 40 mg/day of a GnRH
antagonist if the concentration of AMH in the sample isolated from
the patient is below the AMH reference range. For instance, the
method may include determining that the patient be administered
less than 40 mg/day of relugolix if the concentration of AMH in the
sample isolated from the patient is below the AMH reference
range.
[0051] In some embodiments, the method includes determining that
the patient be administered from about 50 mg/day to about 200
mg/day of a GnRH antagonist if the concentration of AMH in the
sample isolated from the patient is below the AMH reference range.
For instance, the method may include determining that the patient
be administered about 50 mg/day, 75 mg/day, 100 mg/day, or 200
mg/day of a thieno[3,4d]pyrimidine derivative or variant, such as
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or the
choline salt thereof if the concentration of AMH in the sample
isolated from the patient is below the AMH reference range.
[0052] In some embodiments, the method includes determining that
the patient be administered less than 150 mg/day of a GnRH
antagonist if the concentration of AMH in the sample isolated from
the patient is below the AMH reference range. For instance, the
method may include determining that the patient be administered
less than 150 mg/day of elagolix if the concentration of AMH in the
sample isolated from the patient is below the AMH reference range.
In some embodiments, the method includes determining that the
patient be administered less than 400 mg/day of a GnRH antagonist
if the concentration of AMH in the sample isolated from the patient
is below the AMH reference range. For instance, the method may
include determining that the patient be administered less than 400
mg/day of elagolix if the concentration of AMH in the sample
isolated from the patient is below the AMH reference range. In some
embodiments, the method includes administering the GnRH antagonist
to the patient at the determined dose.
[0053] In some embodiments, the method includes determining that
the patient be administered from 10 to 500 mg/day of a GnRH
antagonist if the concentration of AMH in the sample isolated from
the patient is within the AMH reference range. For instance, in
some embodiments, the method includes determining that the patient
be administered from 10 to 490 mg/day, from 25 to 480 mg/day, from
50 to 470 mg/day, or from 100 to 460 mg/day (e.g., 10 mg/day, 15
mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 45
mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75
mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105
mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day,
135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, 160
mg/day, 165 mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day,
190 mg/day, 195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, 215
mg/day, 220 mg/day, 225 mg/day, 230 mg/day, 235 mg/day, 240 mg/day,
245 mg/day, 250 mg/day, 255 mg/day, 260 mg/day, 265 mg/day, 270
mg/day, 275 mg/day, 280 mg/day, 285 mg/day, 290 mg/day, 295 mg/day,
300 mg/day, 305 mg/day, 310 mg/day, 315 mg/day, 320 mg/day, 325
mg/day, 330 mg/day, 335 mg/day, 340 mg/day, 345 mg/day, 350 mg/day,
355 mg/day, 360 mg/day, 365 mg/day, 370 mg/day, 375 mg/day, 380
mg/day, 385 mg/day, 390 mg/day, 395 mg/day, 400 mg/day, 405 mg/day,
410 mg/day, 415 mg/day, 420 mg/day, 425 mg/day, 430 mg/day, 435
mg/day, 440 mg/day, 445 mg/day, 450 mg/day, 455 mg/day, 460 mg/day,
465 mg/day, 470 mg/day, 475 mg/day, 480 mg/day, 485 mg/day, 490
mg/day, 495 mg/day, or 500 mg/day) of a GnRH antagonist if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range.
[0054] In some embodiments, the method includes determining that
the patient be administered 10 mg/day of a GnRH antagonist if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range. For instance, the method may
include determining that the patient be administered 10 mg/day of
ASP-1707 if the concentration of AMH in the sample isolated from
the patient is within the AMH reference range.
[0055] In some embodiments, the method includes determining that
the patient be administered 40 mg/day of a GnRH antagonist if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range. For instance, the method may
include determining that the patient be administered 40 mg/day of
relugolix if the concentration of AMH in the sample isolated from
the patient is within the AMH reference range.
[0056] In some embodiments, the method includes determining that
the patient be administered from about 50 mg/day to about 200
mg/day of a GnRH antagonist if the concentration of AMH in the
sample isolated from the patient is within the AMH reference range.
For instance, the method may include determining that the patient
be administered about 50 mg/day, 75 mg/day, 100 mg/day, or 200
mg/day of a thieno[3,4d]pyrimidine derivative or variant, such as
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid or the
choline salt thereof if the concentration of AMH in the sample
isolated from the patient is within the AMH reference range.
[0057] In some embodiments, the method includes determining that
the patient be administered 150 mg/day of a GnRH antagonist if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range. For instance, the method may
include determining that the patient be administered 150 mg/day of
elagolix if the concentration of AMH in the sample isolated from
the patient is within the AMH reference range. In some embodiments,
the method includes determining that the patient be administered
400 mg/day of a GnRH antagonist if the concentration of AMH in the
sample isolated from the patient is within the AMH reference range.
For instance, the method may include determining that the patient
be administered 400 mg/day of elagolix if the concentration of AMH
in the sample isolated from the patient is within the AMH reference
range. In some embodiments, the method includes administering the
GnRH antagonist to the patient at the determined dose.
[0058] In some embodiments, the AMH reference range is from 15 to
35 pM. Thus, it will be appreciated that an AMH concentration of
less than 15 pM (e.g., 1 pM, 2 pM, 3 pM, 4 pM, 5 pM, 6 pM, 7 pM, 8
pM, 9 pM, 10 pM, 11 pM, 12 pM, 13 pM, or 14 pM) is considered below
an AMH reference range of from 15 to 35 pM. Likewise, an AMH
concentration of greater than 35 pM (e.g., 36 pM, 37 pM, 38 pM, 39
pM, 40 pM, 50 pM, 55 pM, or greater) is considered above an AMH
reference range of from 15 to 35 pM.
[0059] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to reduce or
alleviate a symptom of the endometriosis.
[0060] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to reduce
the serum concentration of .beta.17-estradiol (E2) in the patient
to between about 20 and about 50 pg/ml (e.g., to about 20 pg/ml, 25
pg/ml, 30 pg/ml, 35 pg/ml, 40 pg/ml, 45 pg/ml, or 50 pg/ml). In
some embodiments, the serum concentration of E2 is reduced to
between about 20 and about 50 pg/ml within about 4 to about 36
weeks of administering the GnRH antagonist to the patient (e.g.,
within about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks,
10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16
weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks,
23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29
weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks,
or 36 weeks of administering the GnRH antagonist to the patient).
In some embodiments, the serum concentration of E2 is reduced to
between about 20 and about 50 pg/ml within about 4 weeks of
administering the GnRH antagonist to the patient. In some
embodiments, the serum concentration of E2 is reduced to between
about 20 and about 50 pg/ml within about 12 weeks of administering
the GnRH antagonist to the patient. In some embodiments, the serum
concentration of E2 is reduced to between about 20 and about 50
pg/ml within about 24 weeks of administering the GnRH antagonist to
the patient.
[0061] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to reduce
the serum concentration of follicle stimulating hormone (FSH) in
the patient to between about 0.1 and about 10 mIU/ml (e.g., to
about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5,
6, 7, 8, 9, or 10 mIU/ml). In some embodiments, the serum
concentration of FSH is reduced to between about 0.1 and about 10
mIU/ml within about 4 to about 36 weeks of administering the GnRH
antagonist to the patient (e.g., within about 4 weeks, 5 weeks, 6
weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13
weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks,
20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26
weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks,
33 weeks, 34 weeks, 35 weeks, or 36 weeks of administering the GnRH
antagonist to the patient). In some embodiments, the serum
concentration of FSH is reduced to between about 0.1 and about 10
mIU/mL within about 4 weeks of administering the GnRH antagonist to
the patient. In some embodiments, the serum concentration of FSH is
reduced to between about 0.1 and about 10 mIU/mL within about 12
weeks of administering the GnRH antagonist to the patient. In some
embodiments, the serum concentration of FSH is reduced to between
about 0.1 and about 10 mIU/mL within about 24 weeks of
administering the GnRH antagonist to the patient.
[0062] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to reduce
the serum concentration of luteinizing hormone (LH) in the patient
to between about 0.1 and about 10 mIU/ml (e.g., to about 0.1, 0.2,
0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
mIU/ml). In some embodiments, the serum concentration of LH is
reduced to between about 0.1 and about 10 mIU/mL within about 4 to
about 36 weeks of administering the GnRH antagonist to the patient
(e.g., within about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9
weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks,
16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22
weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks,
29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35
weeks, or 36 weeks of administering the GnRH antagonist to the
patient). In some embodiments, the serum concentration of LH is
reduced to between about 0.1 and about 10 mIU/mL within about 4
weeks of administering the GnRH antagonist to the patient. In some
embodiments, the serum concentration of LH is reduced to between
about 0.1 and about 10 mIU/mL within about 12 weeks of
administering the GnRH antagonist to the patient. In some
embodiments, the serum concentration of LH is reduced to between
about 0.1 and about 10 mIU/mL within about 24 weeks of
administering the GnRH antagonist to the patient.
[0063] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to reduce
endometriosis-associated pain in the patient. In some embodiments,
the endometriosis-associated pain is reduced within about 4 to
about 36 weeks of administering the GnRH antagonist to the patient
(e.g., within about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9
weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks,
16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22
weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks,
29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35
weeks, or 36 weeks of administering the GnRH antagonist to the
patient). In some embodiments, the endometriosis-associated pain is
reduced within about 4 weeks of administering the GnRH antagonist
to the patient. In some embodiments, the endometriosis-associated
pain is reduced within about 12 weeks of administering the GnRH
antagonist to the patient. In some embodiments, the
endometriosis-associated pain is reduced within about 24 weeks of
administering the GnRH antagonist to the patient. In some
embodiments, the endometriosis-associated pain is selected from the
group consisting of pelvic pain, dyspareunia, and dyschezia.
[0064] In some embodiments, the endometriosis-associated pain is
assessed by determining a Numerical Rating Score (NRS) for the
patient. In some embodiments, the NRS is reduced by from about 1%
to about 50% (e.g., by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%). In some
embodiments the NRS is reduced by about 30%.
[0065] In some embodiments, the endometriosis-associated pain is
assessed by determining a Verbal Rating Score (VRS) for the
patient. In some embodiments, the VRS is reduced by from about 1%
to about 50% (e.g., by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%). In some
embodiments the VRS is reduced by about 30%.
[0066] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to alleviate
a symptom selected from the group consisting of dysmenorrhea,
non-menstrual pelvic pain, and dyspareunia. In some embodiments,
the symptom is alleviated within about 4 to about 36 weeks of
administering the GnRH antagonist to the patient (e.g., within
about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10
weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks,
17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23
weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks,
30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, or 36
weeks of administering the GnRH antagonist to the patient). In some
embodiments, the symptom is alleviated within about 4 weeks of
administering the GnRH antagonist to the patient. In some
embodiments, the symptom is alleviated within about 12 weeks of
administering the GnRH antagonist to the patient. In some
embodiments, the symptom is alleviated within about 24 weeks of
administering the GnRH antagonist to the patient.
[0067] In some embodiments, the symptom is assessed by determining
a Biberoglu and Behrman (B&B) scale score for the patient. In
some embodiments, the B&B score is reduced by from about 1% to
about 50% (e.g., by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%).
[0068] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to reduce an
Endometriosis Health Profile-5 (EHP-5) score determined for the
patient. In some embodiments, the EHP-5 score is reduced within
about 4 to about 36 weeks of administering the GnRH antagonist to
the patient (e.g., within about 4 weeks, 5 weeks, 6 weeks, 7 weeks,
8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks,
15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21
weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks,
28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34
weeks, 35 weeks, or 36 weeks of administering the GnRH antagonist
to the patient). In some embodiments, the EHP-5 score is reduced
within about 4 weeks of administering the GnRH antagonist to the
patient. In some embodiments, the EHP-5 score is reduced within
about 12 weeks of administering the GnRH antagonist to the patient.
In some embodiments, the EHP-5 score is reduced within about 24
weeks of administering the GnRH antagonist to the patient. In some
embodiments, the EHP-5 score is reduced by from about 1% to about
50% (e.g., by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%,
20%, 25%, 30%, 35%, 40%, 45%, or 50%).
[0069] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount that does not cause a
reduction in bone mineral density (BMD) in the patient of greater
than 5%. In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount that does not cause a
reduction in BMD in the patient of greater than 1%.
[0070] In some embodiments, the method includes administering
add-back therapy to the patient. The add-back therapy may be
administered to the patient concurrently with the GnRH antagonist,
prior to administration of the GnRH antagonist, or following
administration of the GnRH antagonist. In some embodiments,
add-back therapy is administered as a fixed dose combination
containing a GnRH antagonist, estrogen, and one or more additional
agents, such as a progestin, in a single pharmaceutical
composition. For instance, add-back therapy may be administered as
a fixed dose combination of a GnRH antagonist, estrogen (e.g., in
the form of .beta.17-estradiol, ethinyl estradiol, or a conjugated
estrogen, such as a conjugated equine estrogen) and/or a progestin
(e.g., norethindrone or a compound that is metabolized in vivo to
produce norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate (also referred to herein as "NETA"), among
other agents, such as progesterone, norgestimate,
medroxyprogesterone, and drospirenone) in the form of a single
pharmaceutical composition, such as a single tablet, capsule, gel
cap, powder, liquid solution, or liquid suspension. In some
embodiments, the add-back therapy is administered orally,
transdermally, or intravaginally.
[0071] In some embodiments, the add-back therapy is administered to
the patient in one or more doses per day, week, month, or year,
such as daily, for example, from 1 to 10 times daily, or more
(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, times daily). In
some embodiments, the add-back therapy is administered to the
patient once daily, for example, concurrently with the GnRH
antagonist. For example, the GnRH antagonist may be administered to
the patient orally, and concurrently with oral administration of
the GnRH antagonist, the add-back therapy may be administered to
the patient orally, transdermally, or intravaginally. In some
embodiments, the add-back therapy is administered to the patient in
the form of a pharmaceutical composition that further includes the
GnRH antagonist, such as a single tablet, capsule, gel cap, powder,
liquid solution, or liquid suspension, for instance, as described
above and herein.
[0072] In some embodiments, the add-back therapy is administered to
the patient once daily, following administration of the compound.
For example, the GnRH antagonist may be administered to the patient
orally, and following oral administration of the GnRH antagonist,
the add-back therapy may be administered to the patient orally,
transdermally, or intravaginally.
[0073] In some embodiments, the add-back therapy is administered to
the patient once daily, prior to administration of the compound.
For example, the GnRH antagonist may be administered to the patient
orally, and prior to oral administration of the GnRH antagonist,
the add-back therapy may be administered to the patient orally,
transdermally, or intravaginally.
[0074] In some embodiments, the add-back therapy includes an
estrogen. In some embodiments, the estrogen is selected from the
group consisting of .beta.17-estradiol, ethinyl estradiol, and
conjugated estrogens, such as conjugated equine estrogens.
[0075] In some embodiments, the estrogen is .beta.17-estradiol. The
.beta.17-estradiol may be administered to the patient, for example,
at a dose of from about 0.1 mg to about 2.5 mg, such as at a dose
of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg,
0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6
mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg,
or 2.5 mg, for instance, by oral administration. In some
embodiments, the .beta.17-estradiol is administered to the patient
at a dose of 1.0 mg, for instance, by oral administration. In some
embodiments, the .beta.17-estradiol is administered to the patient
at a dose of 0.5 mg, for instance, by oral administration.
[0076] The .beta.17-estradiol may be administered to the patient
one or more times per day, week, or month. The .beta.17-estradiol
may be administered to the patient, for example, at a dose of from
about 0.1 mg/day to about 2.5 mg/day, such as at a dose of about
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6
mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day,
1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7
mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2 mg/day,
2.3 mg/day, 2.4 mg/day, or 2.5 mg/day, for instance, by oral
administration. In some embodiments, the .beta.17-estradiol is
administered to the patient ata dose of 1.0 mg/day, for instance,
by oral administration. In some embodiments, the .beta.17-estradiol
is administered to the patient at a dose of 0.5 mg/day, for
instance, by oral administration.
[0077] In some embodiments, the estrogen is ethinyl estradiol. The
ethinyl estradiol may be administered to the patient, for example,
at a dose of from about 1.0 .mu.g to about 6.0 .mu.g, such as at a
dose of about 1.0 .mu.g, 1.1 .mu.g, 1.2 .mu.g, 1.3 .mu.g, 1.4
.mu.g, 1.5 .mu.g, 1.6 .mu.g, 1.7 .mu.g, 1.8 .mu.g, 1.9 .mu.g, 2.0
.mu.g, 2.1 .mu.g, 2.2 .mu.g, 2.3 .mu.g, 2.4 .mu.g, 2.5 .mu.g, 2.6
.mu.g, 2.7 .mu.g, 2.8 .mu.g, 2.9 .mu.g, 3.0 .mu.g, 3.1 .mu.g, 3.2
.mu.g, 3.3 .mu.g, 3.4 .mu.g, 3.5 .mu.g, 3.6 .mu.g, 3.7 .mu.g, 3.8
.mu.g, 3.9 .mu.g, 4.0 .mu.g, 4.1 .mu.g, 4.2 .mu.g, 4.2 .mu.g, 4.3
.mu.g, 4.4 .mu.g, 4.5 .mu.g, 4.6 .mu.g, 4.7 .mu.g, 4.8 .mu.g, 4.9
.mu.g, 5.0 .mu.g, 5.1 .mu.g, 5.2 .mu.g, 5.3 .mu.g, 5.4 .mu.g, 5.5
.mu.g, 5.6 .mu.g, 5.7 .mu.g, 5.8 .mu.g, 5.9 .mu.g, or 6.0 .mu.g,
for instance, by oral administration. In some embodiments, the
ethinyl estradiol is administered to the patient at a dose of 5.0
.mu.g, for instance, by oral administration. In some embodiments,
the ethinyl estradiol is administered to the patient at a dose of
2.5 .mu.g, for instance, by oral administration.
[0078] The ethinyl estradiol may be administered to the patient one
or more times per day, week, or month. The ethinyl estradiol may be
administered to the patient, for example, at a dose of from about
1.0 .mu.g/day to about 6.0 .mu.g/day, such as at a dose of about
1.0 .mu.g/day, 1.1 .mu.g/day, 1.2 .mu.g/day, 1.3 .mu.g/day, 1.4
.mu.g/day, 1.5 .mu.g/day, 1.6 .mu.g/day, 1.7 .mu.g/day, 1.8
.mu.g/day, 1.9 .mu.g/day, 2.0 .mu.g/day, 2.1 .mu.g/day, 2.2
.mu.g/day, 2.3 .mu.g/day, 2.4 .mu.g/day, 2.5 .mu.g/day, 2.6
.mu.g/day, 2.7 .mu.g/day, 2.8 .mu.g/day, 2.9 .mu.g/day, 3.0
.mu.g/day, 3.1 .mu.g/day, 3.2 .mu.g/day, 3.3 .mu.g/day, 3.4
.mu.g/day, 3.5 .mu.g/day, 3.6 .mu.g/day, 3.7 .mu.g/day, 3.8
.mu.g/day, 3.9 .mu.g/day, 4.0 .mu.g/day, 4.1 .mu.g/day, 4.2
.mu.g/day, 4.2 .mu.g/day, 4.3 .mu.g/day, 4.4 .mu.g/day, 4.5
.mu.g/day, 4.6 .mu.g/day, 4.7 .mu.g/day, 4.8 .mu.g/day, 4.9
.mu.g/day, 5.0 .mu.g/day, 5.1 .mu.g/day, 5.2 .mu.g/day, 5.3
.mu.g/day, 5.4 .mu.g/day, 5.5 .mu.g/day, 5.6 .mu.g/day, 5.7
.mu.g/day, 5.8 .mu.g/day, 5.9 .mu.g/day, or 6.0 .mu.g/day, for
instance, by oral administration. In some embodiments, the ethinyl
estradiol is administered to the patient at a dose of 5.0
.mu.g/day, for instance, by oral administration. In some
embodiments, the ethinyl estradiol is administered to the patient
at a dose of 2.5 .mu.g/day, for instance, by oral
administration.
[0079] In some embodiments, the estrogen is a conjugated estrogen,
such as a conjugated equine estrogen. The conjugated estrogen may
be administered to the patient, for example, at a dose of from
about 0.1 mg to about 2.0 mg, such as at a dose of about 0.1 mg,
0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0
mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg,
1.9 mg, or 2.0 mg, for instance, by oral administration. In some
embodiments, the conjugated estrogen is administered to the patient
at a dose of 0.625 mg, for instance, by oral administration. In
some embodiments, the conjugated estrogen is administered to the
patient at a dose of 0.45 mg, for instance, by oral administration.
In some embodiments, the conjugated estrogen is administered to the
patient at a dose of 0.3 mg, for instance, by oral
administration.
[0080] The conjugated estrogen may be administered to the patient
one or more times per day, week, or month. The conjugated estrogen
may be administered to the patient, for example, at a dose of from
about 0.1 mg/day to about 2.0 mg/day, such as at a dose of about
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6
mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day,
1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7
mg/day, 1.8 mg/day, 1.9 mg/day, or 2.0 mg/day, for instance, by
oral administration. In some embodiments, the conjugated estrogen
is administered to the patient at a dose of 0.625 mg/day, for
instance, by oral administration. In some embodiments, the
conjugated estrogen is administered to the patient at a dose of
0.45 mg/day, for instance, by oral administration. In some
embodiments, the conjugated estrogen is administered to the patient
at a dose of 0.3 mg/day, for instance, by oral administration.
[0081] In some embodiments, the add-back therapy includes a
progestin. In some embodiments, the progestin is selected from the
group consisting of norethindrone or an ester thereof, such as
norethindrone acetate, or another agent such as progesterone,
norgestimate, medroxyprogesterone, or drospirenone.
[0082] In some embodiments, the progestin is norethindrone or a
compound that is metabolized in vivo to produce norethindrone, such
as an ester of norethindrone that is de-esterified in vivo to
produce norethindrone, for instance, norethindrone acetate.
[0083] In some embodiments, the progestin is norethindrone. The
norethindrone may be administered to the patient, for example, at a
dose of from about 0.05 mg to about 5.0 mg, such as at a dose of
about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg,
0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1
mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg,
2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8
mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg,
3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5
mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 1.0 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 0.5 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 0.1 mg, for instance, by
oral administration.
[0084] The norethindrone may be administered to the patient one or
more times per day, week, or month. The norethindrone may be
administered to the patient, for example, at a dose of from about
0.05 mg/day to about 5.0 mg/day, such as at a dose of about 0.05
mg/day, 0.06 mg/day, 0.07 mg/day, 0.08 mg/day, 0.09 mg/day, 0.1
mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day,
0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day, 1.2
mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7 mg/day,
1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2 mg/day, 2.3
mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day, 2.7 mg/day, 2.8 mg/day,
2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2 mg/day, 3.3 mg/day, 3.4
mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day, 3.8 mg/day, 3.9 mg/day,
4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3 mg/day, 4.4 mg/day, 4.5
mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day, 4.9 mg/day, or 5.0
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 1.0
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 0.5
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 0.1
mg/day, for instance, by oral administration.
[0085] In some embodiments, the progestin is norethindrone acetate.
The norethindrone acetate may be administered to the patient, for
example, at a dose of from about 0.05 mg to about 5.0 mg, such as
at a dose of about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1
mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg,
1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8
mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg,
2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5
mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg,
4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, for
instance, by oral administration. In some embodiments, the
norethindrone acetate is administered to the patient at a dose of
1.0 mg/day, for instance, by oral administration. In some
embodiments, the norethindrone acetate is administered to the
patient at a dose of 0.5 mg, for instance, by oral administration.
In some embodiments, the norethindrone acetate is administered to
the patient at a dose of 0.1 mg, for instance, by oral
administration.
[0086] The norethindrone acetate may be administered to the patient
one or more times per day, week, or month. The norethindrone
acetate may be administered to the patient, for example, at a dose
of from about 0.05 mg/day to about 5.0 mg/day, such as at a dose of
about 0.05 mg/day, 0.06 mg/day, 0.07 mg/day, 0.08 mg/day, 0.09
mg/day, 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day,
0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1
mg/day, 1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day,
1.7 mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2
mg/day, 2.3 mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day, 2.7 mg/day,
2.8 mg/day, 2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2 mg/day, 3.3
mg/day, 3.4 mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day, 3.8 mg/day,
3.9 mg/day, 4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3 mg/day, 4.4
mg/day, 4.5 mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day, 4.9 mg/day,
or 5.0 mg/day, for instance, by oral administration. In some
embodiments, the norethindrone acetate is administered to the
patient at a dose of 1.0 mg/day, for instance, by oral
administration. In some embodiments, the norethindrone acetate is
administered to the patient at a dose of 0.5 mg/day, for instance,
by oral administration. In some embodiments, the norethindrone
acetate is administered to the patient at a dose of 0.1 mg/day, for
instance, by oral administration.
[0087] In some embodiments, the progestin is progesterone. The
progesterone may be administered to the patient, for example, at a
dose of from about 50 mg to about 250 mg, such as a dose of about
50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95
mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg,
140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180
mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg,
225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg, for instance, by
oral administration. In some embodiments, the progesterone is
administered to the patient at a dose of 200 mg, for instance, by
oral administration. In some embodiments, the progesterone is
administered to the patient at a dose of 100 mg, for instance, by
oral administration.
[0088] The progesterone may be administered to the patient one or
more times per day, week, or month. The progesterone may be
administered to the patient, for example, at a dose of from about
50 mg/day to about 250 mg/day, such as a dose of about 50 mg/day,
55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day,
85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110
mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day,
140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, 160 mg/day, 165
mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day, 190 mg/day,
195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, 215 mg/day, 220
mg/day, 225 mg/day, 230 mg/day, 235 mg/day, 240 mg/day, 245 mg/day,
or 250 mg/day, for instance, by oral administration. In some
embodiments, the progesterone is administered to the patient at a
dose of 200 mg/day, for instance, by oral administration. In some
embodiments, the progesterone is administered to the patient at a
dose of 100 mg/day, for instance, by oral administration.
[0089] In some embodiments, the progestin is norgestimate. The
norgestimate may be administered to the patient, for example, at a
dose of from about 0.01 mg to about 2.0 mg, such as at a dose of
about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07
mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6
mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg,
1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg, for instance, by
oral administration. In some embodiments, the norgestimate is
administered to the patient at a dose of 0.09 mg, for instance, by
oral administration.
[0090] The norgestimate may be administered to the patient one or
more times per day, week, or month. The norgestimate may be
administered to the patient, for example, at a dose of from about
0.01 mg/day to about 2.0 mg/day, such as at a dose of about 0.01
mg/day, 0.02 mg/day, 0.03 mg/day, 0.04 mg/day, 0.05 mg/day, 0.06
mg/day, 0.07 mg/day, 0.08 mg/day, 0.09 mg/day, 0.1 mg/day, 0.2
mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day, 0.7 mg/day,
0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day, 1.2 mg/day, 1.3
mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7 mg/day, 1.8 mg/day,
1.9 mg/day, or 2.0 mg/day, for instance, by oral administration. In
some embodiments, the norgestimate is administered to the patient
at a dose of 0.09 mg/day, for instance, by oral administration.
[0091] In some embodiments, the progestin is medroxyprogesterone.
The medroxyprogesterone may be administered to the patient, for
example, at a dose of from about 0.5 mg to about 10.0 mg, such as
at a dose of about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg,
1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9
mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg,
2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6
mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg,
4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3
mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6.0 mg, 6.1 mg,
6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0
mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg,
7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7
mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg,
9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg, for instance, by oral
administration. In some embodiments, the medroxyprogesterone is
administered to the patient at a dose of 5.0 mg, for instance, by
oral administration. In some embodiments, the medroxyprogesterone
is administered to the patient at a dose of 2.5 mg, for instance,
by oral administration. In some embodiments, the
medroxyprogesterone is administered to the patient at a dose of 1.5
mg, for instance, by oral administration.
[0092] The medroxyprogesterone may be administered to the patient
one or more times per day, week, or month. The medroxyprogesterone
may be administered to the patient, for example, at a dose of from
about 0.5 mg/day to about 10.0 mg/day, such as at a dose of about
0.5 mg/day, 0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0
mg/day, 1.1 mg/day, 1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day,
1.6 mg/day, 1.7 mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1
mg/day, 2.2 mg/day, 2.3 mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day,
2.7 mg/day, 2.8 mg/day, 2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2
mg/day, 3.3 mg/day, 3.4 mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day,
3.8 mg/day, 3.9 mg/day, 4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3
mg/day, 4.4 mg/day, 4.5 mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day,
4.9 mg/day, 5.0 mg/day, 5.1 mg/day, 5.2 mg/day, 5.3 mg/day, 5.4
mg/day, 5.5 mg/day, 5.6 mg/day, 5.7 mg/day, 5.8 mg/day, 5.9 mg/day,
6.0 mg/day, 6.1 mg/day, 6.2 mg/day, 6.3 mg/day, 6.4 mg/day, 6.5
mg/day, 6.6 mg/day, 6.7 mg/day, 6.8 mg/day, 6.9 mg/day, 7.0 mg/day,
7.1 mg/day, 7.2 mg/day, 7.3 mg/day, 7.4 mg/day, 7.5 mg/day, 7.6
mg/day, 7.7 mg/day, 7.8 mg/day, 7.9 mg/day, 8.0 mg/day, 8.1 mg/day,
8.2 mg/day, 8.3 mg/day, 8.4 mg/day, 8.5 mg/day, 8.6 mg/day, 8.7
mg/day, 8.8 mg/day, 8.9 mg/day, 9.0 mg/day, 9.1 mg/day, 9.2 mg/day,
9.3 mg/day, 9.4 mg/day, 9.5 mg/day, 9.6 mg/day, 9.7 mg/day, 9.8
mg/day, 9.9 mg/day, or 10.0 mg/day, for instance, by oral
administration. In some embodiments, the medroxyprogesterone is
administered to the patient at a dose of 5.0 mg/day, for instance,
by oral administration. In some embodiments, the
medroxyprogesterone is administered to the patient at a dose of 2.5
mg/day, for instance, by oral administration. In some embodiments,
the medroxyprogesterone is administered to the patient at a dose of
1.5 mg/day, for instance, by oral administration.
[0093] In some embodiments, the progestin is drospirenone. The
drospirenone may be administered to the patient, for example, at a
dose of from about 0.1 mg to about 1.0 mg, such as at a dose of
about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8
mg, 0.9 mg, or 1.0 mg, for instance, by oral administration. In
some embodiments, the drospirenone is administered to the patient
at a dose of 0.5 mg, for instance, by oral administration. In some
embodiments, the drospirenone is administered to the patient at a
dose of 0.25 mg, for instance, by oral administration.
[0094] The drospirenone may be administered to the patient one or
more times per day, week, or month. The drospirenone may be
administered to the patient, for example, at a dose of from about
0.1 mg/day to about 1.0 mg/day, such as at a dose of about 0.1
mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day,
0.7 mg/day, 0.8 mg/day, 0.9 mg/day, or 1.0 mg/day, for instance, by
oral administration. In some embodiments, the drospirenone is
administered to the patient at a dose of 0.5 mg/day, for instance,
by oral administration. In some embodiments, the drospirenone is
administered to the patient at a dose of 0.25 mg/day, for instance,
by oral administration.
[0095] In some embodiments, the add-back therapy includes an
estrogen and a progestin. In some embodiments, the add-back therapy
includes .beta.17-estradiol and norethindrone or a compound that is
metabolized in vivo to produce norethindrone, such as an ester of
norethindrone that is de-esterified in vivo to produce
norethindrone, for instance, norethindrone acetate.
[0096] In some embodiments, the add-back therapy includes from
about 0.75 mg to about 1.25 mg of .beta.17-estradiol, e.g.,
administered orally, and from about 0.25 mg to about 0.75 mg of
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate, e.g., administered orally. In some
embodiments, the add-back therapy includes 1.0 mg of
.beta.17-estradiol, e.g., administered orally, and 0.5 mg of
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate, e.g., administered orally. In some
embodiments, the add-back therapy includes 1.0 mg of
.beta.17-estradiol, e.g., administered orally, and, in the same
pharmaceutical composition, 0.5 mg of norethindrone or a compound
that is metabolized in vivo to produce norethindrone, such as an
ester of norethindrone that is de-esterified in vivo to produce
norethindrone, for instance, norethindrone acetate, e.g.,
administered orally. In some embodiments, the add-back therapy
includes 1.0 mg of .beta.17-estradiol, e.g., administered orally,
and, in a separate pharmaceutical composition, 0.5 mg of
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate, e.g., administered orally.
[0097] In some embodiments, the GnRH antagonist is a compound
represented by formula (I), (II), or (III), herein, and is
administered to the patient in a fixed-dose composition that
contains about 50 mg, 75 mg, 100 mg, or 200 mg of the compound,
from about 0.75 mg to about 1.25 mg of .beta.17-estradiol, and from
about 0.25 mg to about 0.75 mg of norethindrone or a compound that
is metabolized in vivo to produce norethindrone, such as an ester
of norethindrone that is de-esterified in vivo to produce
norethindrone, for instance, norethindrone acetate. In some
embodiments, the compound is administered to the patient in a
fixed-dose composition that contains about 50 mg, 75 mg, 100 mg, or
200 mg of the compound, about 1.0 mg of .beta.17-estradiol (e.g.,
1.0 mg of .beta.17-estradiol), and about 0.5 mg of norethindrone or
a compound that is metabolized in vivo to produce norethindrone,
such as an ester of norethindrone that is de-esterified in vivo to
produce norethindrone, for instance, norethindrone acetate (e.g.,
0.5 mg of norethindrone or a compound that is metabolized in vivo
to produce norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate).
[0098] In some embodiments, the above fixed-dose composition is
administered to the patient in one or more doses per 12 hours, 24
hours, 48 hours, 72 hours, week, month, or year, such as in from 1
to 10 doses per 12 hours (e.g., 1 dose every 12 hours, 2 doses
every 12 hours, 3 doses every 12 hours, 4 doses every 12 hours, 5
doses every 12 hours, 6 doses every 12 hours, 7 doses every 12
hours, 8 doses every 12 hours, 9 doses every 12 hours, or 10 doses
every 12 hours), from 1 to 10 doses per 24 hours (e.g., 1 dose
every 24 hours, 2 doses every 24 hours, 3 doses every 24 hours, 4
doses every 24 hours, 5 doses every 24 hours, 6 doses every 24
hours, 7 doses every 24 hours, 8 doses every 24 hours, 9 doses
every 24 hours, or 10 doses every 24 hours), from 1 to 10 doses per
48 hours (e.g., 1 dose every 48 hours, 2 doses every 48 hours, 3
doses every 48 hours, 4 doses every 48 hours, 5 doses every 48
hours, 6 doses every 48 hours, 7 doses every 48 hours, 8 doses
every 48 hours, 9 doses every 48 hours, or 10 doses every 48
hours), from 1 to 10 doses per 72 hours (e.g., 1 dose every 72
hours, 2 doses every 72 hours, 3 doses every 72 hours, 4 doses
every 72 hours, 5 doses every 72 hours, 6 doses every 72 hours, 7
doses every 72 hours, 8 doses every 72 hours, 9 doses every 72
hours, or 10 doses every 72 hours), from 1 to 10 doses per week
(e.g., 1 dose every week, 2 doses every week, 3 doses every week, 4
doses every week, 5 doses every week, 6 doses every week, 7 doses
every week, 8 doses every week, 9 doses every week, or 10 doses
every week), or from 1 to 60 doses per month (e.g., from 30-60
doses per month, such as 1 time daily, 2 times daily, 3 times
daily, 4 times daily, 5 times daily, 6 times daily, 7 times daily,
8 times daily, 9 times daily, 10 times daily, 7 times weekly, 8
times weekly, 9 times weekly, 10 times weekly, 11 times weekly, 12
times weekly, 13 times weekly, 14 times weekly, or more), among
others. In some embodiments, the above fixed-dose composition is
administered to the patient once daily.
[0099] In some embodiments, the add-back therapy includes from
about 0.25 mg to about 0.75 mg of .beta.17-estradiol, e.g.,
administered orally, and from about 0.05 mg to about 0.2 mg of
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate, e.g., administered orally. In some
embodiments, the add-back therapy includes 0.5 mg of
.beta.17-estradiol, e.g., administered orally, and 0.1 mg of
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate, e.g., administered orally. In some
embodiments, the add-back therapy includes 0.5 mg of
.beta.17-estradiol, e.g., administered orally, and, in the same
pharmaceutical composition, 0.1 mg of norethindrone or a compound
that is metabolized in vivo to produce norethindrone, such as an
ester of norethindrone that is de-esterified in vivo to produce
norethindrone, for instance, norethindrone acetate, e.g.,
administered orally. In some embodiments, the add-back therapy
includes 0.5 mg of .beta.17-estradiol, e.g., administered orally,
and, in a separate pharmaceutical composition, 0.1 mg of
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate, e.g., administered orally.
[0100] In some embodiments, the GnRH antagonist is a compound
represented by formula (I), (II), or (III), herein, and is
administered to the patient in a fixed-dose composition that
contains about 50 mg, 75 mg, 100 mg, or 200 mg of the compound,
from about 0.25 mg to about 0.75 mg of .beta.17-estradiol, and from
about 0.05 mg to about 0.2 mg of norethindrone or a compound that
is metabolized in vivo to produce norethindrone, such as an ester
of norethindrone that is de-esterified in vivo to produce
norethindrone, for instance, norethindrone acetate. In some
embodiments, the compound is administered to the patient in a
fixed-dose composition that contains about 50 mg, 75 mg, 100 mg, or
200 mg of the compound, about 0.5 mg of .beta.17-estradiol (e.g.,
0.5 mg of .beta.17-estradiol), and about 0.1 mg of norethindrone or
a compound that is metabolized in vivo to produce norethindrone,
such as an ester of norethindrone that is de-esterified in vivo to
produce norethindrone, for instance, norethindrone acetate (e.g.,
0.1 mg of norethindrone or a compound that is metabolized in vivo
to produce norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate).
[0101] In some embodiments, the above fixed-dose composition is
administered to the patient in one or more doses per 12 hours, 24
hours, 48 hours, 72 hours, week, month, or year, such as in from 1
to 10 doses per 12 hours (e.g., 1 dose every 12 hours, 2 doses
every 12 hours, 3 doses every 12 hours, 4 doses every 12 hours, 5
doses every 12 hours, 6 doses every 12 hours, 7 doses every 12
hours, 8 doses every 12 hours, 9 doses every 12 hours, or 10 doses
every 12 hours), from 1 to 10 doses per 24 hours (e.g., 1 dose
every 24 hours, 2 doses every 24 hours, 3 doses every 24 hours, 4
doses every 24 hours, 5 doses every 24 hours, 6 doses every 24
hours, 7 doses every 24 hours, 8 doses every 24 hours, 9 doses
every 24 hours, or 10 doses every 24 hours), from 1 to 10 doses per
48 hours (e.g., 1 dose every 48 hours, 2 doses every 48 hours, 3
doses every 48 hours, 4 doses every 48 hours, 5 doses every 48
hours, 6 doses every 48 hours, 7 doses every 48 hours, 8 doses
every 48 hours, 9 doses every 48 hours, or 10 doses every 48
hours), from 1 to 10 doses per 72 hours (e.g., 1 dose every 72
hours, 2 doses every 72 hours, 3 doses every 72 hours, 4 doses
every 72 hours, 5 doses every 72 hours, 6 doses every 72 hours, 7
doses every 72 hours, 8 doses every 72 hours, 9 doses every 72
hours, or 10 doses every 72 hours), from 1 to 10 doses per week
(e.g., 1 dose every week, 2 doses every week, 3 doses every week, 4
doses every week, 5 doses every week, 6 doses every week, 7 doses
every week, 8 doses every week, 9 doses every week, or 10 doses
every week), from 1 to 60 doses per month (e.g., from 30-60 doses
per month, such as 1 time daily, 2 times daily, 3 times daily, 4
times daily, 5 times daily, 6 times daily, 7 times daily, 8 times
daily, 9 times daily, 10 times daily, 7 times weekly, 8 times
weekly, 9 times weekly, 10 times weekly, 11 times weekly, 12 times
weekly, 13 times weekly, 14 times weekly, or more), among others.
In some embodiments, the fixed-dose composition is administered to
the patient once daily.
[0102] In some embodiments, the patient does not exhibit a
reduction in BMD of greater than 5% following administration of the
GnRH antagonist and the add-back therapy. In some embodiments, the
patient does not exhibit a reduction in BMD of greater than 1%
following administration of the GnRH antagonist and the add-back
therapy. The add-back therapy may be formulated for oral
administration. For instance, the add-back therapy may be
formulated as a tablet, capsule, gel cap, powder, liquid solution,
or liquid suspension. In some embodiments, the add-back therapy
includes both an estrogen, such as .beta.17-estradiol, and a
progestin, such as norethindrone or norethindrone acetate. The
estrogen and progestin may be administered separately or admixed in
a single composition, such as a single tablet, capsule, gel cap,
powder, liquid solution, or liquid suspension.
[0103] In some embodiments, the BMD is assessed by dual energy
X-ray absorptiometry. In some embodiments, the BMD is assessed in
the spine or femur of the patient.
[0104] In some embodiments, the GnRH antagonist is a compound
represented by formula (I)
##STR00001##
[0105] wherein ring A is a thiophene ring;
[0106] each R.sup.A is independently a halogen atom, a cyano group,
a nitro group, an optionally substituted lower alkyl group, an
optionally substituted lower alkenyl group, an optionally
substituted lower alkynyl group, a hydroxyiminomethyl group, an
optionally substituted sulfonyl group, an optionally substituted
sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1,
COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3,
CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to
W.sup.3 independently are a hydrogen atom or an optionally
substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind
together with the neighboring nitrogen atom to form an optionally
substituted cyclic amino group;
[0107] m is an integer from 0 to 3;
[0108] ring B is an aryl group or a monocyclic heteroaryl
group;
[0109] each R.sup.B is independently a halogen atom, a cyano group,
an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4,
COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6
independently are a hydrogen atom or an optionally substituted
lower alkyl group, or W.sup.5 and W.sup.6 may bind together with
the neighboring nitrogen atom to form an optionally substituted
cyclic amino group;
[0110] n is an integer from 0 to 2;
[0111] U is a single bond;
[0112] X is a group represented by --S-L-Y, --O-L-Y, --CO-L-Y, or
--SO.sub.2-L-Y, wherein L is an optionally substituted lower
alkylene group;
[0113] Y is a group represented by Z or --NW.sup.7W.sup.8, wherein
W.sup.7 and W.sup.8 independently are a hydrogen atom, an
optionally substituted lower alkyl group, or Z with the proviso
that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or
W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen
atom to form an optionally substituted cyclic amino group;
[0114] Z is an optionally fused and optionally substituted
cycloalkyl group, an optionally fused and optionally substituted
heterocycloalkyl group, an optionally fused and optionally
substituted aryl group, or an optionally fused and optionally
substituted heteroaryl group;
[0115] or a pharmaceutically acceptable salt thereof.
[0116] In some embodiments, the ring A is a thiophene ring
represented by formula (A)
##STR00002##
[0117] In some embodiments, m is 1 or 2. In some embodiments, m is
1. For instance, the ring A may be an optionally substituted
thiophene ring represented by formula (B)
##STR00003##
[0118] Each R.sup.A may independently be, for example, a halogen
atom (e.g., fluorine, chlorine, bromine, or iodine), an optionally
substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3,
wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an
optionally substituted lower alkyl group, or W.sup.2 and W.sup.3
may bind together with the neighboring nitrogen atom to form an
optionally substituted cyclic amino group. In some embodiments,
each R.sup.A is COOH or pharmaceutically acceptable salt
thereof.
[0119] In some embodiments, ring B is an optionally substituted
benzene ring, pyridine ring, or thiophene ring. For instance, ring
B may be represented by a formula selected from the group
consisting of:
##STR00004##
[0120] In some embodiments, n is 1 or 2. For instance, in some
embodiments, n is 1. Ring B may be, for example, represented by a
formula selected from the group consisting of:
##STR00005##
[0121] In some embodiments, each R.sup.B is independently a halogen
atom, an optionally substituted lower alkyl group, or OW.sup.4,
wherein each W.sup.4 is independently a hydrogen atom or an
optionally substituted lower alkyl group. For instance, each
R.sup.B may be independently a fluorine atom, chlorine atom,
bromine atom, methyl group, or methoxy group.
[0122] In some embodiments, U is a single bond. X may be, for
example, a group represented by --O-L-Y. L may be, for example, a
methylene group. In some embodiments, Y is an optionally
substituted benzene ring represented by formula (C)
##STR00006##
[0123] wherein each R.sup.C is independently a halogen atom, an
optionally substituted lower alkyl group, or OW.sup.9, wherein each
W.sup.9 is independently a hydrogen atom or an optionally
substituted lower alkyl group; and
[0124] p is an integer from 0 to 3.
[0125] In some embodiments, Y is a substituted benzene ring
represented by formula (D)
##STR00007##
[0126] In some embodiments, the compound is represented by formula
(II)
##STR00008##
or a pharmaceutically acceptable salt thereof.
[0127] In some embodiments, the compound is the choline salt of the
compound represented by formula (II), i.e., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate.
[0128] In some embodiments, the GnRH antagonist includes the
compound represented by formula (II) in a crystalline state. In
some embodiments, the compound exhibits characteristic X-ray powder
diffraction peaks at about 7.1.degree. 2.theta., 11.5.degree.
2.theta., 19.4.degree. 2.theta., 20.3.degree. 2.theta.,
21.5.degree. 2.theta., 22.0.degree. 2.theta., 22.6.degree.
2.theta., 23.5.degree. 2.theta., and 26.2.degree. 2.theta.. In some
embodiments, the compound exhibits .sup.13C solid-state nuclear
magnetic resonance (NMR) peaks centered at about 155.8 ppm, 149.8
ppm, 145.3 ppm, 118.0 ppm, 113.7 ppm, 111.6 ppm, 110.3 ppm, 98.1
ppm, 69.8 ppm, 58.7 ppm, 57.1 ppm, and 55.5 ppm. In some
embodiments, the compound exhibits .sup.19F solid-state NMR peaks
centered at about -131.6 ppm, -145.2 ppm, and -151.8 ppm.
[0129] In some embodiments, the method includes administering from
about 50 mg/day to about 200 mg/day (e.g., 50 mg/day, 55 mg/day, 60
mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90
mg/day, 95 mg/day, 100 mg/day, 110 mg/day, 115 mg/day, 120 mg/day,
125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150
mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day,
180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day, or 200 mg/day) of
the compound represented by formula (I), or a pharmaceutically
acceptable salt thereof, to the patient if the concentration of AMH
in the sample isolated from the patient is above the AMH reference
range.
[0130] In some embodiments, the method includes administering about
50 mg/day of the compound represented by formula (I), or a
pharmaceutically acceptable salt thereof, to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range.
[0131] In some embodiments, the method includes administering about
75 mg/day of the compound represented by formula (I), or a
pharmaceutically acceptable salt thereof, to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range.
[0132] In some embodiments, the method includes administering about
100 mg/day of the compound represented by formula (I), or a
pharmaceutically acceptable salt thereof, to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range.
[0133] In some embodiments, the method includes administering about
200 mg/day of the compound represented by formula (I), or a
pharmaceutically acceptable salt thereof, to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range.
[0134] In some embodiments, the method includes administering from
50 mg/day to about 200 mg/day (e.g., 50 mg/day, 55 mg/day, 60
mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90
mg/day, 95 mg/day, 100 mg/day, 110 mg/day, 115 mg/day, 120 mg/day,
125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150
mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day,
180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day, or 200 mg/day) of
the compound represented by formula (II) to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range.
[0135] In some embodiments, the method includes administering about
50 mg/day of the compound represented by formula (II), or a
pharmaceutically acceptable salt thereof, such as the choline salt
thereof, to the patient if the concentration of AMH in the sample
isolated from the patient is above the AMH reference range.
[0136] In some embodiments, the method includes administering about
75 mg/day of the compound represented by formula (II), or a
pharmaceutically acceptable salt thereof, such as the choline salt
thereof, to the patient if the concentration of AMH in the sample
isolated from the patient is above the AMH reference range.
[0137] In some embodiments, the method includes administering about
100 mg/day of the compound represented by formula (II), or a
pharmaceutically acceptable salt thereof, such as the choline salt
thereof, to the patient if the concentration of AMH in the sample
isolated from the patient is above the AMH reference range.
[0138] In some embodiments, the method includes administering about
200 mg/day of the compound represented by formula (II), or a
pharmaceutically acceptable salt thereof, such as the choline salt
thereof, to the patient if the concentration of AMH in the sample
isolated from the patient is above the AMH reference range.
[0139] In some embodiments, the method includes administering from
about 50 mg/day to about 200 mg/day (e.g., 50 mg/day, 55 mg/day, 60
mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90
mg/day, 95 mg/day, 100 mg/day, 110 mg/day, 115 mg/day, 120 mg/day,
125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150
mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day,
180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day, or 200 mg/day) of
the compound represented by formula (I), or a pharmaceutically
acceptable salt thereof, to the patient if the concentration of AMH
in the sample isolated from the patient is below the AMH reference
range.
[0140] In some embodiments, the method includes administering about
50 mg/day of the compound represented by formula (I), or a
pharmaceutically acceptable salt thereof, to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range.
[0141] In some embodiments, the method includes administering about
75 mg/day of the compound represented by formula (I), or a
pharmaceutically acceptable salt thereof, to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range.
[0142] In some embodiments, the method includes administering about
100 mg/day of the compound represented by formula (I), or a
pharmaceutically acceptable salt thereof, to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range.
[0143] In some embodiments, the method includes administering about
200 mg/day of the compound represented by formula (I), or a
pharmaceutically acceptable salt thereof, to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range.
[0144] In some embodiments, the method includes administering from
50 mg/day to about 200 mg/day (e.g., 50 mg/day, 55 mg/day, 60
mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90
mg/day, 95 mg/day, 100 mg/day, 110 mg/day, 115 mg/day, 120 mg/day,
125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150
mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day,
180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day, or 200 mg/day) of
the compound represented by formula (II) to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range.
[0145] In some embodiments, the method includes administering about
50 mg/day of the compound represented by formula (II), or a
pharmaceutically acceptable salt thereof, such as the choline salt
thereof, to the patient if the concentration of AMH in the sample
isolated from the patient is below the AMH reference range.
[0146] In some embodiments, the method includes administering about
75 mg/day of the compound represented by formula (II), or a
pharmaceutically acceptable salt thereof, such as the choline salt
thereof, to the patient if the concentration of AMH in the sample
isolated from the patient is below the AMH reference range.
[0147] In some embodiments, the method includes administering about
100 mg/day of the compound represented by formula (II), or a
pharmaceutically acceptable salt thereof, such as the choline salt
thereof, to the patient if the concentration of AMH in the sample
isolated from the patient is below the AMH reference range.
[0148] In some embodiments, the method includes administering about
200 mg/day of the compound represented by formula (II), or a
pharmaceutically acceptable salt thereof, such as the choline salt
thereof, to the patient if the concentration of AMH in the sample
isolated from the patient is below the AMH reference range.
[0149] In some embodiments, the method includes administering from
about 50 mg/day to about 200 mg/day (e.g., 50 mg/day, 55 mg/day, 60
mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90
mg/day, 95 mg/day, 100 mg/day, 110 mg/day, 115 mg/day, 120 mg/day,
125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150
mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day,
180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day, or 200 mg/day) of
the compound represented by formula (I), or a pharmaceutically
acceptable salt thereof, to the patient if the concentration of AMH
in the sample isolated from the patient is within the AMH reference
range.
[0150] In some embodiments, the method includes administering about
50 mg/day of the compound represented by formula (I), or a
pharmaceutically acceptable salt thereof, to the patient if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range.
[0151] In some embodiments, the method includes administering about
75 mg/day of the compound represented by formula (I), or a
pharmaceutically acceptable salt thereof, to the patient if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range.
[0152] In some embodiments, the method includes administering about
100 mg/day of the compound represented by formula (I), or a
pharmaceutically acceptable salt thereof, to the patient if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range.
[0153] In some embodiments, the method includes administering about
200 mg/day of the compound represented by formula (I), or a
pharmaceutically acceptable salt thereof, to the patient if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range.
[0154] In some embodiments, the method includes administering from
50 mg/day to about 200 mg/day (e.g., 50 mg/day, 55 mg/day, 60
mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90
mg/day, 95 mg/day, 100 mg/day, 110 mg/day, 115 mg/day, 120 mg/day,
125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150
mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day,
180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day, or 200 mg/day) of
the compound represented by formula (II) to the patient if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range.
[0155] In some embodiments, the method includes administering about
50 mg/day of the compound represented by formula (II), or a
pharmaceutically acceptable salt thereof, such as the choline salt
thereof, to the patient if the concentration of AMH in the sample
isolated from the patient is within the AMH reference range.
[0156] In some embodiments, the method includes administering about
75 mg/day of the compound represented by formula (II), or a
pharmaceutically acceptable salt thereof, such as the choline salt
thereof, to the patient if the concentration of AMH in the sample
isolated from the patient is within the AMH reference range.
[0157] In some embodiments, the method includes administering about
100 mg/day of the compound represented by formula (II), or a
pharmaceutically acceptable salt thereof, such as the choline salt
thereof, to the patient if the concentration of AMH in the sample
isolated from the patient is within the AMH reference range.
[0158] In some embodiments, the method includes administering about
200 mg/day of the compound represented by formula (II), or a
pharmaceutically acceptable salt thereof, such as the choline salt
thereof, to the patient if the concentration of AMH in the sample
isolated from the patient is within the AMH reference range.
[0159] In some embodiments, the method includes administering from
40 to 225 mg/day (e.g., 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day,
60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day,
90 mg/day, 95 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 175
mg/day, or 200 mg/day) of the compound represented by formula (I)
to the patient if the concentration of AMH in the sample isolated
from the patient is above the AMH reference range. In some
embodiments, the method includes administering 50 mg/day, 75
mg/day, 100 mg/day, or 200 mg/day of the compound represented by
formula (I) to the patient if the concentration of AMH in the
sample isolated from the patient is above the AMH reference range.
In some embodiments, the method includes administering from 40 to
225 mg/day (e.g., 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60
mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90
mg/day, 95 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 175 mg/day,
or 200 mg/day) of the compound represented by formula (II) to the
patient if the concentration of AMH in the sample isolated from the
patient is above the AMH reference range. In some embodiments, the
method includes administering 50 mg/day, 75 mg/day, 100 mg/day, or
200 mg/day of the compound represented by formula (II) to the
patient if the concentration of AMH in the sample isolated from the
patient is above the AMH reference range. In some embodiments, the
method includes administering from 40 to 225 mg/day (e.g., 40
mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70
mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100
mg/day, 125 mg/day, 150 mg/day, 175 mg/day, or 200 mg/day) of
choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate to
the patient if the concentration of AMH in the sample isolated from
the patient is above the AMH reference range. In some embodiments,
the method includes administering 50 mg/day, 75 mg/day, 100 mg/day,
or 200 mg/day of choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate to
the patient if the concentration of AMH in the sample isolated from
the patient is above the AMH reference range.
[0160] In some embodiments, the method includes administering from
40 to 225 mg/day (e.g., 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day,
60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day,
90 mg/day, 95 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 175
mg/day, or 200 mg/day) of the compound represented by formula (I)
to the patient if the concentration of AMH in the sample isolated
from the patient is below the AMH reference range. In some
embodiments, the method includes administering 50 mg/day, 75
mg/day, 100 mg/day, or 200 mg/day of the compound represented by
formula (I) to the patient if the concentration of AMH in the
sample isolated from the patient is below the AMH reference range.
In some embodiments, the method includes administering from 40 to
225 mg/day (e.g., 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60
mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90
mg/day, 95 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 175 mg/day,
or 200 mg/day) of the compound represented by formula (II) to the
patient if the concentration of AMH in the sample isolated from the
patient is below the AMH reference range. In some embodiments, the
method includes administering 50 mg/day, 75 mg/day, 100 mg/day, or
200 mg/day of the compound represented by formula (II) to the
patient if the concentration of AMH in the sample isolated from the
patient is below the AMH reference range. In some embodiments, the
method includes administering from 40 to 225 mg/day (e.g., 40
mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70
mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100
mg/day, 125 mg/day, 150 mg/day, 175 mg/day, or 200 mg/day) of
choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate to
the patient if the concentration of AMH in the sample isolated from
the patient is below the AMH reference range. In some embodiments,
the method includes administering 50 mg/day, 75 mg/day, 100 mg/day,
or 200 mg/day of choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate to
the patient if the concentration of AMH in the sample isolated from
the patient is below the AMH reference range.
[0161] In some embodiments, the method includes administering from
40 to 225 mg/day (e.g., 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day,
60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day,
90 mg/day, 95 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 175
mg/day, or 200 mg/day) of the compound represented by formula (I)
to the patient if the concentration of AMH in the sample isolated
from the patient is within the AMH reference range. In some
embodiments, the method includes administering 50 mg/day, 75
mg/day, 100 mg/day, or 200 mg/day of the compound represented by
formula (I) to the patient if the concentration of AMH in the
sample isolated from the patient is within the AMH reference range.
In some embodiments, the method includes administering from 40 to
225 mg/day (e.g., 40 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60
mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90
mg/day, 95 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 175 mg/day,
or 200 mg/day) of the compound represented by formula (II) to the
patient if the concentration of AMH in the sample isolated from the
patient is within the AMH reference range. In some embodiments, the
method includes administering 50 mg/day, 75 mg/day, 100 mg/day, or
200 mg/day of the compound represented by formula (II) to the
patient if the concentration of AMH in the sample isolated from the
patient is within the AMH reference range. In some embodiments, the
method includes administering from 40 to 225 mg/day (e.g., 40
mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70
mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100
mg/day, 125 mg/day, 150 mg/day, 175 mg/day, or 200 mg/day) of
choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate to the
patient if the concentration of AMH in the sample isolated from the
patient is within the AMH reference range. In some embodiments, the
method includes administering 50 mg/day, 75 mg/day, 100 mg/day, or
200 mg/day of choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate to the
patient if the concentration of AMH in the sample isolated from the
patient is within the AMH reference range.
[0162] In some embodiments, the GnRH antagonist is selected from
the group consisting of elagolix, relugolix, ASP-1707, SKI2670, and
BAY-784, or a derivative or variant thereof.
[0163] In some embodiments, the GnRH antagonist is elagolix or a
derivative or variant thereof, such as a compound described in U.S.
Pat. No. 7,056,927; 7,176,211; 7,419,983; 8,765,948; or 9,382,214;
or in US Patent Application Publication No. 2014/0288031 or
2017/0056403, the disclosures of which are incorporated herein by
reference in their entirety. In some embodiments, the method
includes administering 150 mg/day or more (e.g., 150 mg/day, 155
mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day, 180 mg/day,
185 mg/day, 190 mg/day, 195 mg/day, 200 mg/day, 205 mg/day, 210
mg/day, 215 mg/day, 220 mg/day, 225 mg/day, 230 mg/day, 235 mg/day,
240 mg/day, 245 mg/day, 250 mg/day, 255 mg/day, 260 mg/day, 265
mg/day, 270 mg/day, 275 mg/day, 280 mg/day, 285 mg/day, 290 mg/day,
295 mg/day, 300 mg/day, 305 mg/day, 310 mg/day, 315 mg/day, 320
mg/day, 325 mg/day, 330 mg/day, 335 mg/day, 340 mg/day, 345 mg/day,
350 mg/day, 355 mg/day, 360 mg/day, 365 mg/day, 370 mg/day, 375
mg/day, 380 mg/day, 385 mg/day, 390 mg/day, 395, 400 mg/day, or
more) of elagolix to the patient if the concentration of AMH in the
sample isolated from the patient is above the AMH reference range.
In some embodiments, the method includes administering from 145
mg/day to 405 mg/day of elagolix to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range.
[0164] In some embodiments, the method includes administering more
than 400 mg/day (e.g., 405 mg/day, 410 mg/day, 415 mg/day, 420
mg/day, 425 mg/day, 430 mg/day, 435 mg/day, 440 mg/day, 445 mg/day,
450 mg/day, 455 mg/day, 460 mg/day, 465 mg/day, 470 mg/day, 475
mg/day, 480 mg/day, 485 mg/day, 490 mg/day, 495 mg/day, 500 mg/day,
505 mg/day, 510 mg/day, 515 mg/day, 520 mg/day, 525 mg/day, 530
mg/day, 535 mg/day, 540 mg/day, 545 mg/day, 550 mg/day, 555 mg/day,
560 mg/day, 565 mg/day, 570 mg/day, 575 mg/day, 580 mg/day, 585
mg/day, 590 mg/day, 595 mg/day, 600 mg/day, 605 mg/day, 610 mg/day,
615 mg/day, 620 mg/day, 625 mg/day, 630 mg/day, 635 mg/day, 640
mg/day, 645 mg/day, 650 mg/day, 655 mg/day, 660 mg/day, 665 mg/day,
670 mg/day, 675 mg/day, 680 mg/day, 685 mg/day, 690 mg/day, 695
mg/day, 700 mg/day, or more) of elagolix to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range. In some embodiments, the method
includes administering from 400 mg/day to 600 mg/day of elagolix to
the patient if the concentration of AMH in the sample isolated from
the patient is above the AMH reference range.
[0165] When administered at elevated doses (for instance, doses of
150 mg/day, 400 mg/day, or more) elagolix may be administered in
combination with add-back therapy. The add-back therapy may be
administered to the patient concurrently with the elagolix, prior
to administration of the elagolix, or following administration of
the elagolix.
[0166] In some embodiments, the add-back therapy includes an
estrogen. In some embodiments, the estrogen is selected from the
group consisting of .beta.17-estradiol, ethinyl estradiol, and
conjugated estrogens, such as conjugated equine estrogens.
[0167] In some embodiments, the estrogen is .beta.17-estradiol. The
.beta.17-estradiol may be administered to the patient, for example,
at a dose of from about 0.1 mg to about 2.5 mg, such as at a dose
of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg,
0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6
mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg,
or 2.5 mg, for instance, by oral administration. In some
embodiments, the .beta.17-estradiol is administered to the patient
at a dose of 1.0 mg, for instance, by oral administration. In some
embodiments, the .beta.17-estradiol is administered to the patient
at a dose of 0.5 mg, for instance, by oral administration.
[0168] The .beta.17-estradiol may be administered to the patient
one or more times per day, week, or month. The .beta.17-estradiol
may be administered to the patient, for example, at a dose of from
about 0.1 mg/day to about 2.5 mg/day, such as at a dose of about
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6
mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day,
1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7
mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2 mg/day,
2.3 mg/day, 2.4 mg/day, or 2.5 mg/day, for instance, by oral
administration. In some embodiments, the .beta.17-estradiol is
administered to the patient at a dose of 1.0 mg/day, for instance,
by oral administration. In some embodiments, the .beta.17-estradiol
is administered to the patient at a dose of 0.5 mg/day, for
instance, by oral administration.
[0169] In some embodiments, the estrogen is ethinyl estradiol. The
ethinyl estradiol may be administered to the patient, for example,
at a dose of from about 1.0 .mu.g to about 6.0 .mu.g, such as at a
dose of about 1.0 .mu.g, 1.1 .mu.g, 1.2 .mu.g, 1.3 .mu.g, 1.4
.mu.g, 1.5 .mu.g, 1.6 .mu.g, 1.7 .mu.g, 1.8 .mu.g, 1.9 .mu.g, 2.0
.mu.g, 2.1 .mu.g, 2.2 .mu.g, 2.3 .mu.g, 2.4 .mu.g, 2.5 .mu.g, 2.6
.mu.g, 2.7 .mu.g, 2.8 .mu.g, 2.9 .mu.g, 3.0 .mu.g, 3.1 .mu.g, 3.2
.mu.g, 3.3 .mu.g, 3.4 .mu.g, 3.5 .mu.g, 3.6 .mu.g, 3.7 .mu.g, 3.8
.mu.g, 3.9 .mu.g, 4.0 .mu.g, 4.1 .mu.g, 4.2 .mu.g, 4.2 .mu.g, 4.3
.mu.g, 4.4 .mu.g, 4.5 .mu.g, 4.6 .mu.g, 4.7 .mu.g, 4.8 .mu.g, 4.9
.mu.g, 5.0 .mu.g, 5.1 .mu.g, 5.2 .mu.g, 5.3 .mu.g, 5.4 .mu.g, 5.5
.mu.g, 5.6 .mu.g, 5.7 .mu.g, 5.8 .mu.g, 5.9 .mu.g, or 6.0 .mu.g,
for instance, by oral administration. In some embodiments, the
ethinyl estradiol is administered to the patient at a dose of 5.0
.mu.g, for instance, by oral administration. In some embodiments,
the ethinyl estradiol is administered to the patient at a dose of
2.5 .mu.g, for instance, by oral administration.
[0170] The ethinyl estradiol may be administered to the patient one
or more times per day, week, or month. The ethinyl estradiol may be
administered to the patient, for example, at a dose of from about
1.0 .mu.g/day to about 6.0 .mu.g/day, such as at a dose of about
1.0 .mu.g/day, 1.1 .mu.g/day, 1.2 .mu.g/day, 1.3 .mu.g/day, 1.4
.mu.g/day, 1.5 .mu.g/day, 1.6 .mu.g/day, 1.7 .mu.g/day, 1.8
.mu.g/day, 1.9 .mu.g/day, 2.0 .mu.g/day, 2.1 .mu.g/day, 2.2
.mu.g/day, 2.3 .mu.g/day, 2.4 .mu.g/day, 2.5 .mu.g/day, 2.6
.mu.g/day, 2.7 .mu.g/day, 2.8 .mu.g/day, 2.9 .mu.g/day, 3.0
.mu.g/day, 3.1 .mu.g/day, 3.2 .mu.g/day, 3.3 .mu.g/day, 3.4
.mu.g/day, 3.5 .mu.g/day, 3.6 .mu.g/day, 3.7 .mu.g/day, 3.8
.mu.g/day, 3.9 .mu.g/day, 4.0 .mu.g/day, 4.1 .mu.g/day, 4.2
.mu.g/day, 4.2 .mu.g/day, 4.3 .mu.g/day, 4.4 .mu.g/day, 4.5
.mu.g/day, 4.6 .mu.g/day, 4.7 .mu.g/day, 4.8 .mu.g/day, 4.9
.mu.g/day, 5.0 .mu.g/day, 5.1 .mu.g/day, 5.2 .mu.g/day, 5.3
.mu.g/day, 5.4 .mu.g/day, 5.5 .mu.g/day, 5.6 .mu.g/day, 5.7
.mu.g/day, 5.8 .mu.g/day, 5.9 .mu.g/day, or 6.0 .mu.g/day, for
instance, by oral administration. In some embodiments, the ethinyl
estradiol is administered to the patient at a dose of 5.0
.mu.g/day, for instance, by oral administration. In some
embodiments, the ethinyl estradiol is administered to the patient
at a dose of 2.5 .mu.g/day, for instance, by oral
administration.
[0171] In some embodiments, the estrogen is a conjugated estrogen,
such as a conjugated equine estrogen. The conjugated estrogen may
be administered to the patient, for example, at a dose of from
about 0.1 mg to about 2.0 mg, such as at a dose of about 0.1 mg,
0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0
mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg,
1.9 mg, or 2.0 mg, for instance, by oral administration. In some
embodiments, the conjugated estrogen is administered to the patient
at a dose of 0.625 mg, for instance, by oral administration. In
some embodiments, the conjugated estrogen is administered to the
patient at a dose of 0.45 mg, for instance, by oral administration.
In some embodiments, the conjugated estrogen is administered to the
patient at a dose of 0.3 mg, for instance, by oral
administration.
[0172] The conjugated estrogen may be administered to the patient
one or more times per day, week, or month. The conjugated estrogen
may be administered to the patient, for example, at a dose of from
about 0.1 mg/day to about 2.0 mg/day, such as at a dose of about
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6
mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day,
1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7
mg/day, 1.8 mg/day, 1.9 mg/day, or 2.0 mg/day, for instance, by
oral administration. In some embodiments, the conjugated estrogen
is administered to the patient at a dose of 0.625 mg/day, for
instance, by oral administration. In some embodiments, the
conjugated estrogen is administered to the patient at a dose of
0.45 mg/day, for instance, by oral administration. In some
embodiments, the conjugated estrogen is administered to the patient
at a dose of 0.3 mg/day, for instance, by oral administration.
[0173] In some embodiments, the add-back therapy includes a
progestin. In some embodiments, the progestin is selected from the
group consisting of norethindrone or an ester thereof, such as
norethindrone acetate, or another agent such as progesterone,
norgestimate, medroxyprogesterone, or drospirenone.
[0174] In some embodiments, the progestin is norethindrone or a
compound that is metabolized in vivo to produce norethindrone, such
as an ester of norethindrone that is de-esterified in vivo to
produce norethindrone, for instance, norethindrone acetate.
[0175] In some embodiments, the progestin is norethindrone. The
norethindrone may be administered to the patient, for example, at a
dose of from about 0.05 mg to about 5.0 mg, such as at a dose of
about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg,
0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1
mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg,
2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8
mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg,
3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5
mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 1.0 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 0.5 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 0.1 mg, for instance, by
oral administration.
[0176] The norethindrone may be administered to the patient one or
more times per day, week, or month. The norethindrone may be
administered to the patient, for example, at a dose of from about
0.05 mg/day to about 5.0 mg/day, such as at a dose of about 0.05
mg/day, 0.06 mg/day, 0.07 mg/day, 0.08 mg/day, 0.09 mg/day, 0.1
mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day,
0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day, 1.2
mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7 mg/day,
1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2 mg/day, 2.3
mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day, 2.7 mg/day, 2.8 mg/day,
2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2 mg/day, 3.3 mg/day, 3.4
mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day, 3.8 mg/day, 3.9 mg/day,
4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3 mg/day, 4.4 mg/day, 4.5
mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day, 4.9 mg/day, or 5.0
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 1.0
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 0.5
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 0.1
mg/day, for instance, by oral administration.
[0177] In some embodiments, the progestin is norethindrone acetate.
The norethindrone acetate may be administered to the patient, for
example, at a dose of from about 0.05 mg to about 5.0 mg, such as
at a dose of about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1
mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg,
1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8
mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg,
2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5
mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg,
4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, for
instance, by oral administration. In some embodiments, the
norethindrone acetate is administered to the patient at a dose of
1.0 mg/day, for instance, by oral administration. In some
embodiments, the norethindrone acetate is administered to the
patient at a dose of 0.5 mg, for instance, by oral administration.
In some embodiments, the norethindrone acetate is administered to
the patient at a dose of 0.1 mg, for instance, by oral
administration.
[0178] The norethindrone acetate may be administered to the patient
one or more times per day, week, or month. The norethindrone
acetate may be administered to the patient, for example, at a dose
of from about 0.05 mg/day to about 5.0 mg/day, such as at a dose of
about 0.05 mg/day, 0.06 mg/day, 0.07 mg/day, 0.08 mg/day, 0.09
mg/day, 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day,
0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1
mg/day, 1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day,
1.7 mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2
mg/day, 2.3 mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day, 2.7 mg/day,
2.8 mg/day, 2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2 mg/day, 3.3
mg/day, 3.4 mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day, 3.8 mg/day,
3.9 mg/day, 4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3 mg/day, 4.4
mg/day, 4.5 mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day, 4.9 mg/day,
or 5.0 mg/day, for instance, by oral administration. In some
embodiments, the norethindrone acetate is administered to the
patient at a dose of 1.0 mg/day, for instance, by oral
administration. In some embodiments, the norethindrone acetate is
administered to the patient at a dose of 0.5 mg/day, for instance,
by oral administration. In some embodiments, the norethindrone
acetate is administered to the patient at a dose of 0.1 mg/day, for
instance, by oral administration.
[0179] In some embodiments, the progestin is progesterone. The
progesterone may be administered to the patient, for example, at a
dose of from about 50 mg to about 250 mg, such as a dose of about
50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95
mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg,
140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180
mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg,
225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg, for instance, by
oral administration. In some embodiments, the progesterone is
administered to the patient at a dose of 200 mg, for instance, by
oral administration. In some embodiments, the progesterone is
administered to the patient at a dose of 100 mg, for instance, by
oral administration.
[0180] The progesterone may be administered to the patient one or
more times per day, week, or month. The progesterone may be
administered to the patient, for example, at a dose of from about
50 mg/day to about 250 mg/day, such as a dose of about 50 mg/day,
55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day,
85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110
mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day,
140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, 160 mg/day, 165
mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day, 190 mg/day,
195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, 215 mg/day, 220
mg/day, 225 mg/day, 230 mg/day, 235 mg/day, 240 mg/day, 245 mg/day,
or 250 mg/day, for instance, by oral administration. In some
embodiments, the progesterone is administered to the patient at a
dose of 200 mg/day, for instance, by oral administration. In some
embodiments, the progesterone is administered to the patient at a
dose of 100 mg/day, for instance, by oral administration.
[0181] In some embodiments, the progestin is norgestimate. The
norgestimate may be administered to the patient, for example, at a
dose of from about 0.01 mg to about 2.0 mg, such as at a dose of
about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07
mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6
mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg,
1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg, for instance, by
oral administration. In some embodiments, the norgestimate is
administered to the patient at a dose of 0.09 mg, for instance, by
oral administration.
[0182] The norgestimate may be administered to the patient one or
more times per day, week, or month. The norgestimate may be
administered to the patient, for example, at a dose of from about
0.01 mg/day to about 2.0 mg/day, such as at a dose of about 0.01
mg/day, 0.02 mg/day, 0.03 mg/day, 0.04 mg/day, 0.05 mg/day, 0.06
mg/day, 0.07 mg/day, 0.08 mg/day, 0.09 mg/day, 0.1 mg/day, 0.2
mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day, 0.7 mg/day,
0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day, 1.2 mg/day, 1.3
mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7 mg/day, 1.8 mg/day,
1.9 mg/day, or 2.0 mg/day, for instance, by oral administration. In
some embodiments, the norgestimate is administered to the patient
at a dose of 0.09 mg/day, for instance, by oral administration.
[0183] In some embodiments, the progestin is medroxyprogesterone.
The medroxyprogesterone may be administered to the patient, for
example, at a dose of from about 0.5 mg to about 10.0 mg, such as
at a dose of about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg,
1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9
mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg,
2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6
mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg,
4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3
mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6.0 mg, 6.1 mg,
6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0
mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg,
7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7
mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg,
9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg, for instance, by oral
administration. In some embodiments, the medroxyprogesterone is
administered to the patient at a dose of 5.0 mg, for instance, by
oral administration. In some embodiments, the medroxyprogesterone
is administered to the patient at a dose of 2.5 mg, for instance,
by oral administration. In some embodiments, the
medroxyprogesterone is administered to the patient at a dose of 1.5
mg, for instance, by oral administration.
[0184] The medroxyprogesterone may be administered to the patient
one or more times per day, week, or month. The medroxyprogesterone
may be administered to the patient, for example, at a dose of from
about 0.5 mg/day to about 10.0 mg/day, such as at a dose of about
0.5 mg/day, 0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0
mg/day, 1.1 mg/day, 1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day,
1.6 mg/day, 1.7 mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1
mg/day, 2.2 mg/day, 2.3 mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day,
2.7 mg/day, 2.8 mg/day, 2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2
mg/day, 3.3 mg/day, 3.4 mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day,
3.8 mg/day, 3.9 mg/day, 4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3
mg/day, 4.4 mg/day, 4.5 mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day,
4.9 mg/day, 5.0 mg/day, 5.1 mg/day, 5.2 mg/day, 5.3 mg/day, 5.4
mg/day, 5.5 mg/day, 5.6 mg/day, 5.7 mg/day, 5.8 mg/day, 5.9 mg/day,
6.0 mg/day, 6.1 mg/day, 6.2 mg/day, 6.3 mg/day, 6.4 mg/day, 6.5
mg/day, 6.6 mg/day, 6.7 mg/day, 6.8 mg/day, 6.9 mg/day, 7.0 mg/day,
7.1 mg/day, 7.2 mg/day, 7.3 mg/day, 7.4 mg/day, 7.5 mg/day, 7.6
mg/day, 7.7 mg/day, 7.8 mg/day, 7.9 mg/day, 8.0 mg/day, 8.1 mg/day,
8.2 mg/day, 8.3 mg/day, 8.4 mg/day, 8.5 mg/day, 8.6 mg/day, 8.7
mg/day, 8.8 mg/day, 8.9 mg/day, 9.0 mg/day, 9.1 mg/day, 9.2 mg/day,
9.3 mg/day, 9.4 mg/day, 9.5 mg/day, 9.6 mg/day, 9.7 mg/day, 9.8
mg/day, 9.9 mg/day, or 10.0 mg/day, for instance, by oral
administration. In some embodiments, the medroxyprogesterone is
administered to the patient at a dose of 5.0 mg/day, for instance,
by oral administration. In some embodiments, the
medroxyprogesterone is administered to the patient at a dose of 2.5
mg/day, for instance, by oral administration. In some embodiments,
the medroxyprogesterone is administered to the patient at a dose of
1.5 mg/day, for instance, by oral administration.
[0185] In some embodiments, the progestin is drospirenone. The
drospirenone may be administered to the patient, for example, at a
dose of from about 0.1 mg to about 1.0 mg, such as at a dose of
about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8
mg, 0.9 mg, or 1.0 mg, for instance, by oral administration. In
some embodiments, the drospirenone is administered to the patient
at a dose of 0.5 mg, for instance, by oral administration. In some
embodiments, the drospirenone is administered to the patient at a
dose of 0.25 mg, for instance, by oral administration.
[0186] The drospirenone may be administered to the patient one or
more times per day, week, or month. The drospirenone may be
administered to the patient, for example, at a dose of from about
0.1 mg/day to about 1.0 mg/day, such as at a dose of about 0.1
mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day,
0.7 mg/day, 0.8 mg/day, 0.9 mg/day, or 1.0 mg/day, for instance, by
oral administration. In some embodiments, the drospirenone is
administered to the patient at a dose of 0.5 mg/day, for instance,
by oral administration. In some embodiments, the drospirenone is
administered to the patient at a dose of 0.25 mg/day, for instance,
by oral administration.
[0187] In some embodiments, the add-back therapy includes an
estrogen and a progestin. In some embodiments, the add-back therapy
includes .beta.17-estradiol and norethindrone or a compound that is
metabolized in vivo to produce norethindrone, such as an ester of
norethindrone that is de-esterified in vivo to produce
norethindrone, for instance, norethindrone acetate.
[0188] In some embodiments, the patient does not exhibit a
reduction in BMD of greater than 5% following administration of the
elagolix and the add-back therapy. In some embodiments, the patient
does not exhibit a reduction in BMD of greater than 1% following
administration of the elagolix and the add-back therapy. The
add-back therapy may be formulated for oral administration. For
instance, the add-back therapy may be formulated as a tablet,
capsule, gel cap, powder, liquid solution, or liquid suspension. In
some embodiments, the add-back therapy includes both an estrogen,
such as 817-estradiol, and a progestin, such as norethindrone or
norethindrone acetate. The estrogen and progestin may be
administered separately or admixed in a single composition, such as
a single tablet, capsule, gel cap, powder, liquid solution, or
liquid suspension.
[0189] In some embodiments, the method includes administering 400
mg/day, 150 mg/day, or less (e.g., 50 mg/day, 55 mg/day, 60 mg/day,
65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day,
95 mg/day, 100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120
mg/day, 125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, or 145
mg/day) of elagolix to the patient if the concentration of AMH in
the sample isolated from the patient is below the AMH reference
range. In some embodiments, the method includes administering from
50 mg/day to 125 mg/day of elagolix to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range. In some embodiments, the method
includes administering 100 mg/day of elagolix to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range.
[0190] In some embodiments, the method includes administering 400
mg/day or less (e.g., 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day,
70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day,
100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125
mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day,
155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day, 180
mg/day, 185 mg/day, 190 mg/day, 195 mg/day, 200 mg/day, 205 mg/day,
210 mg/day, 215 mg/day, 220 mg/day, 225 mg/day, 230 mg/day, 235
mg/day, 240 mg/day, 245 mg/day, 250 mg/day, 255 mg/day, 260 mg/day,
265 mg/day, 270 mg/day, 275 mg/day, 280 mg/day, 285 mg/day, 290
mg/day, 295 mg/day, 300 mg/day, 305 mg/day, 310 mg/day, 315 mg/day,
320 mg/day, 325 mg/day, 330 mg/day, 335 mg/day, 340 mg/day, 345
mg/day, 350 mg/day, 355 mg/day, 360 mg/day, 365 mg/day, 370 mg/day,
375 mg/day, 380 mg/day, 385 mg/day, 390 mg/day, or 395 mg/day) of
elagolix to the patient if the concentration of AMH in the sample
isolated from the patient is below the AMH reference range. In some
embodiments, the method includes administering from 150 mg/day to
375 mg/day of elagolix to the patient if the concentration of AMH
in the sample isolated from the patient is below the AMH reference
range. In some embodiments, the method includes administering 150
mg/day of elagolix to the patient if the concentration of AMH in
the sample isolated from the patient is below the AMH reference
range.
[0191] In some embodiments, the method includes administering from
150 mg/day to 400 mg/day (e.g., 150 mg/day, 155 mg/day, 160 mg/day,
165 mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day, 190
mg/day, 195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, 215 mg/day,
220 mg/day, 225 mg/day, 230 mg/day, 235 mg/day, 240 mg/day, 245
mg/day, 250 mg/day, 255 mg/day, 260 mg/day, 265 mg/day, 270 mg/day,
275 mg/day, 280 mg/day, 285 mg/day, 290 mg/day, 295 mg/day, 300
mg/day, 305 mg/day, 310 mg/day, 315 mg/day, 320 mg/day, 325 mg/day,
330 mg/day, 335 mg/day, 340 mg/day, 345 mg/day, 350 mg/day, 355
mg/day, 360 mg/day, 365 mg/day, 370 mg/day, 375 mg/day, 380 mg/day,
385 mg/day, 390 mg/day, 395, or 400 mg/day) of elagolix to the
patient if the concentration of AMH in the sample isolated from the
patient is within the AMH reference range. In some embodiments, the
method includes administering 150 mg/day of elagolix to the patient
if the concentration of AMH in the sample isolated from the patient
is within the AMH reference range. In some embodiments, the method
includes administering 400 mg/day of elagolix to the patient if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range. For instance, the method may
include administering 200 mg/day of the elagolix to the patient
twice daily if the concentration of AMH in the sample isolated from
the patient is within the AMH reference range.
[0192] In some embodiments, the GnRH antagonist is relugolix or a
derivative or variant thereof, such as a compound described in U.S.
Pat. No. 7,300,935; 8,058,280; 8,735,401; or 9,346,822; or in US
Patent Application Publication No. 2015/0266891, the disclosures of
which are incorporated herein by reference in their entirety. In
some embodiments, the method includes administering 40 mg/day or
more (e.g., from 40 mg/day to 150 mg/day or more, such as 45
mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75
mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105
mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day,
135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day, or more) of
relugolix to the patient if the concentration of AMH in the sample
isolated from the patient is above the AMH reference range. In some
embodiments, the method includes administering from 50 mg/day to 75
mg/day of relugolix to the patient if the concentration of AMH in
the sample isolated from the patient is above the AMH reference
range.
[0193] In some embodiments, the method includes administering 40
mg/day or less (e.g., from 10 mg/day to 35 mg/day, such as 10
mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, or 35 mg/day)
of relugolix to the patient if the concentration of AMH in the
sample isolated from the patient is below the AMH reference range.
In some embodiments, the method includes administering from 10
mg/day to 30 mg/day of relugolix to the patient if the
concentration of AMH in the sample isolated from the patient is
below the AMH reference range.
[0194] In some embodiments, the method includes administering from
35 mg/day to 45 mg/day (e.g., 35 mg/day, 40 mg/day, or 45 mg/day)
of relugolix to the patient if the concentration of AMH in the
sample isolated from the patient is within the AMH reference range.
In some embodiments, the method includes administering 40 mg/day of
relugolix to the patient if the concentration of AMH in the sample
isolated from the patient is within the AMH reference range.
[0195] When administered at elevated doses (for instance, doses of
40 mg/day or more) relugolix may be administered in combination
with add-back therapy. The add-back therapy may be administered to
the patient concurrently with the relugolix, prior to
administration of the relugolix, or following administration of the
relugolix.
[0196] In some embodiments, the add-back therapy includes an
estrogen. In some embodiments, the estrogen is selected from the
group consisting of .beta.17-estradiol, ethinyl estradiol, and
conjugated estrogens, such as conjugated equine estrogens.
[0197] In some embodiments, the estrogen is .beta.17-estradiol. The
.beta.17-estradiol may be administered to the patient, for example,
at a dose of from about 0.1 mg to about 2.5 mg, such as at a dose
of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg,
0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6
mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg,
or 2.5 mg, for instance, by oral administration. In some
embodiments, the .beta.17-estradiol is administered to the patient
at a dose of 1.0 mg, for instance, by oral administration. In some
embodiments, the .beta.17-estradiol is administered to the patient
at a dose of 0.5 mg, for instance, by oral administration.
[0198] The .beta.17-estradiol may be administered to the patient
one or more times per day, week, or month. The .beta.17-estradiol
may be administered to the patient, for example, at a dose of from
about 0.1 mg/day to about 2.5 mg/day, such as at a dose of about
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6
mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day,
1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7
mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2 mg/day,
2.3 mg/day, 2.4 mg/day, or 2.5 mg/day, for instance, by oral
administration. In some embodiments, the .beta.17-estradiol is
administered to the patient ata dose of 1.0 mg/day, for instance,
by oral administration. In some embodiments, the .beta.17-estradiol
is administered to the patient at a dose of 0.5 mg/day, for
instance, by oral administration.
[0199] In some embodiments, the estrogen is ethinyl estradiol. The
ethinyl estradiol may be administered to the patient, for example,
at a dose of from about 1.0 .mu.g to about 6.0 .mu.g, such as at a
dose of about 1.0 .mu.g, 1.1 .mu.g, 1.2 .mu.g, 1.3 .mu.g, 1.4
.mu.g, 1.5 .mu.g, 1.6 .mu.g, 1.7 .mu.g, 1.8 .mu.g, 1.9 .mu.g, 2.0
.mu.g, 2.1 .mu.g, 2.2 .mu.g, 2.3 .mu.g, 2.4 .mu.g, 2.5 .mu.g, 2.6
.mu.g, 2.7 .mu.g, 2.8 .mu.g, 2.9 .mu.g, 3.0 .mu.g, 3.1 .mu.g, 3.2
.mu.g, 3.3 .mu.g, 3.4 .mu.g, 3.5 .mu.g, 3.6 .mu.g, 3.7 .mu.g, 3.8
.mu.g, 3.9 .mu.g, 4.0 .mu.g, 4.1 .mu.g, 4.2 .mu.g, 4.2 .mu.g, 4.3
.mu.g, 4.4 .mu.g, 4.5 .mu.g, 4.6 .mu.g, 4.7 .mu.g, 4.8 .mu.g, 4.9
.mu.g, 5.0 .mu.g, 5.1 .mu.g, 5.2 .mu.g, 5.3 .mu.g, 5.4 .mu.g, 5.5
.mu.g, 5.6 .mu.g, 5.7 .mu.g, 5.8 .mu.g, 5.9 .mu.g, or 6.0 .mu.g,
for instance, by oral administration. In some embodiments, the
ethinyl estradiol is administered to the patient at a dose of 5.0
.mu.g, for instance, by oral administration. In some embodiments,
the ethinyl estradiol is administered to the patient at a dose of
2.5 .mu.g, for instance, by oral administration.
[0200] The ethinyl estradiol may be administered to the patient one
or more times per day, week, or month. The ethinyl estradiol may be
administered to the patient, for example, at a dose of from about
1.0 .mu.g/day to about 6.0 .mu.g/day, such as at a dose of about
1.0 .mu.g/day, 1.1 .mu.g/day, 1.2 .mu.g/day, 1.3 .mu.g/day, 1.4
.mu.g/day, 1.5 .mu.g/day, 1.6 .mu.g/day, 1.7 .mu.g/day, 1.8
.mu.g/day, 1.9 .mu.g/day, 2.0 .mu.g/day, 2.1 .mu.g/day, 2.2
.mu.g/day, 2.3 .mu.g/day, 2.4 .mu.g/day, 2.5 .mu.g/day, 2.6
.mu.g/day, 2.7 .mu.g/day, 2.8 .mu.g/day, 2.9 .mu.g/day, 3.0
.mu.g/day, 3.1 .mu.g/day, 3.2 .mu.g/day, 3.3 .mu.g/day, 3.4
.mu.g/day, 3.5 .mu.g/day, 3.6 .mu.g/day, 3.7 .mu.g/day, 3.8
.mu.g/day, 3.9 .mu.g/day, 4.0 .mu.g/day, 4.1 .mu.g/day, 4.2
.mu.g/day, 4.2 .mu.g/day, 4.3 .mu.g/day, 4.4 .mu.g/day, 4.5
.mu.g/day, 4.6 .mu.g/day, 4.7 .mu.g/day, 4.8 .mu.g/day, 4.9
.mu.g/day, 5.0 .mu.g/day, 5.1 .mu.g/day, 5.2 .mu.g/day, 5.3
.mu.g/day, 5.4 .mu.g/day, 5.5 .mu.g/day, 5.6 .mu.g/day, 5.7
.mu.g/day, 5.8 .mu.g/day, 5.9 .mu.g/day, or 6.0 .mu.g/day, for
instance, by oral administration. In some embodiments, the ethinyl
estradiol is administered to the patient at a dose of 5.0
.mu.g/day, for instance, by oral administration. In some
embodiments, the ethinyl estradiol is administered to the patient
at a dose of 2.5 .mu.g/day, for instance, by oral
administration.
[0201] In some embodiments, the estrogen is a conjugated estrogen,
such as a conjugated equine estrogen. The conjugated estrogen may
be administered to the patient, for example, at a dose of from
about 0.1 mg to about 2.0 mg, such as at a dose of about 0.1 mg,
0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0
mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg,
1.9 mg, or 2.0 mg, for instance, by oral administration. In some
embodiments, the conjugated estrogen is administered to the patient
at a dose of 0.625 mg, for instance, by oral administration. In
some embodiments, the conjugated estrogen is administered to the
patient at a dose of 0.45 mg, for instance, by oral administration.
In some embodiments, the conjugated estrogen is administered to the
patient at a dose of 0.3 mg, for instance, by oral
administration.
[0202] The conjugated estrogen may be administered to the patient
one or more times per day, week, or month. The conjugated estrogen
may be administered to the patient, for example, at a dose of from
about 0.1 mg/day to about 2.0 mg/day, such as at a dose of about
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6
mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day,
1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7
mg/day, 1.8 mg/day, 1.9 mg/day, or 2.0 mg/day, for instance, by
oral administration. In some embodiments, the conjugated estrogen
is administered to the patient at a dose of 0.625 mg/day, for
instance, by oral administration. In some embodiments, the
conjugated estrogen is administered to the patient at a dose of
0.45 mg/day, for instance, by oral administration. In some
embodiments, the conjugated estrogen is administered to the patient
at a dose of 0.3 mg/day, for instance, by oral administration.
[0203] In some embodiments, the add-back therapy includes a
progestin. In some embodiments, the progestin is selected from the
group consisting of norethindrone or an ester thereof, such as
norethindrone acetate, or another agent such as progesterone,
norgestimate, medroxyprogesterone, or drospirenone.
[0204] In some embodiments, the progestin is norethindrone or a
compound that is metabolized in vivo to produce norethindrone, such
as an ester of norethindrone that is de-esterified in vivo to
produce norethindrone, for instance, norethindrone acetate.
[0205] In some embodiments, the progestin is norethindrone. The
norethindrone may be administered to the patient, for example, at a
dose of from about 0.05 mg to about 5.0 mg, such as at a dose of
about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg,
0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1
mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg,
2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8
mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg,
3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5
mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 1.0 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 0.5 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 0.1 mg, for instance, by
oral administration.
[0206] The norethindrone may be administered to the patient one or
more times per day, week, or month. The norethindrone may be
administered to the patient, for example, at a dose of from about
0.05 mg/day to about 5.0 mg/day, such as at a dose of about 0.05
mg/day, 0.06 mg/day, 0.07 mg/day, 0.08 mg/day, 0.09 mg/day, 0.1
mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day,
0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day, 1.2
mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7 mg/day,
1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2 mg/day, 2.3
mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day, 2.7 mg/day, 2.8 mg/day,
2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2 mg/day, 3.3 mg/day, 3.4
mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day, 3.8 mg/day, 3.9 mg/day,
4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3 mg/day, 4.4 mg/day, 4.5
mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day, 4.9 mg/day, or 5.0
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 1.0
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 0.5
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 0.1
mg/day, for instance, by oral administration.
[0207] In some embodiments, the progestin is norethindrone acetate.
The norethindrone acetate may be administered to the patient, for
example, at a dose of from about 0.05 mg to about 5.0 mg, such as
at a dose of about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1
mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg,
1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8
mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg,
2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5
mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg,
4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, for
instance, by oral administration. In some embodiments, the
norethindrone acetate is administered to the patient at a dose of
1.0 mg/day, for instance, by oral administration. In some
embodiments, the norethindrone acetate is administered to the
patient at a dose of 0.5 mg, for instance, by oral administration.
In some embodiments, the norethindrone acetate is administered to
the patient at a dose of 0.1 mg, for instance, by oral
administration.
[0208] The norethindrone acetate may be administered to the patient
one or more times per day, week, or month. The norethindrone
acetate may be administered to the patient, for example, at a dose
of from about 0.05 mg/day to about 5.0 mg/day, such as at a dose of
about 0.05 mg/day, 0.06 mg/day, 0.07 mg/day, 0.08 mg/day, 0.09
mg/day, 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day,
0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1
mg/day, 1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day,
1.7 mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2
mg/day, 2.3 mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day, 2.7 mg/day,
2.8 mg/day, 2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2 mg/day, 3.3
mg/day, 3.4 mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day, 3.8 mg/day,
3.9 mg/day, 4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3 mg/day, 4.4
mg/day, 4.5 mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day, 4.9 mg/day,
or 5.0 mg/day, for instance, by oral administration. In some
embodiments, the norethindrone acetate is administered to the
patient at a dose of 1.0 mg/day, for instance, by oral
administration. In some embodiments, the norethindrone acetate is
administered to the patient at a dose of 0.5 mg/day, for instance,
by oral administration. In some embodiments, the norethindrone
acetate is administered to the patient at a dose of 0.1 mg/day, for
instance, by oral administration.
[0209] In some embodiments, the progestin is progesterone. The
progesterone may be administered to the patient, for example, at a
dose of from about 50 mg to about 250 mg, such as a dose of about
50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95
mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg,
140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180
mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg,
225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg, for instance, by
oral administration. In some embodiments, the progesterone is
administered to the patient at a dose of 200 mg, for instance, by
oral administration. In some embodiments, the progesterone is
administered to the patient at a dose of 100 mg, for instance, by
oral administration.
[0210] The progesterone may be administered to the patient one or
more times per day, week, or month. The progesterone may be
administered to the patient, for example, at a dose of from about
50 mg/day to about 250 mg/day, such as a dose of about 50 mg/day,
55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day,
85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110
mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day,
140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, 160 mg/day, 165
mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day, 190 mg/day,
195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, 215 mg/day, 220
mg/day, 225 mg/day, 230 mg/day, 235 mg/day, 240 mg/day, 245 mg/day,
or 250 mg/day, for instance, by oral administration. In some
embodiments, the progesterone is administered to the patient at a
dose of 200 mg/day, for instance, by oral administration. In some
embodiments, the progesterone is administered to the patient at a
dose of 100 mg/day, for instance, by oral administration.
[0211] In some embodiments, the progestin is norgestimate. The
norgestimate may be administered to the patient, for example, at a
dose of from about 0.01 mg to about 2.0 mg, such as at a dose of
about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07
mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6
mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg,
1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg, for instance, by
oral administration. In some embodiments, the norgestimate is
administered to the patient at a dose of 0.09 mg, for instance, by
oral administration.
[0212] The norgestimate may be administered to the patient one or
more times per day, week, or month. The norgestimate may be
administered to the patient, for example, at a dose of from about
0.01 mg/day to about 2.0 mg/day, such as at a dose of about 0.01
mg/day, 0.02 mg/day, 0.03 mg/day, 0.04 mg/day, 0.05 mg/day, 0.06
mg/day, 0.07 mg/day, 0.08 mg/day, 0.09 mg/day, 0.1 mg/day, 0.2
mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day, 0.7 mg/day,
0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day, 1.2 mg/day, 1.3
mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7 mg/day, 1.8 mg/day,
1.9 mg/day, or 2.0 mg/day, for instance, by oral administration. In
some embodiments, the norgestimate is administered to the patient
at a dose of 0.09 mg/day, for instance, by oral administration.
[0213] In some embodiments, the progestin is medroxyprogesterone.
The medroxyprogesterone may be administered to the patient, for
example, at a dose of from about 0.5 mg to about 10.0 mg, such as
at a dose of about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg,
1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9
mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg,
2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6
mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg,
4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3
mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6.0 mg, 6.1 mg,
6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0
mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg,
7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7
mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg,
9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg, for instance, by oral
administration. In some embodiments, the medroxyprogesterone is
administered to the patient at a dose of 5.0 mg, for instance, by
oral administration. In some embodiments, the medroxyprogesterone
is administered to the patient at a dose of 2.5 mg, for instance,
by oral administration. In some embodiments, the
medroxyprogesterone is administered to the patient at a dose of 1.5
mg, for instance, by oral administration.
[0214] The medroxyprogesterone may be administered to the patient
one or more times per day, week, or month. The medroxyprogesterone
may be administered to the patient, for example, at a dose of from
about 0.5 mg/day to about 10.0 mg/day, such as at a dose of about
0.5 mg/day, 0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0
mg/day, 1.1 mg/day, 1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day,
1.6 mg/day, 1.7 mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1
mg/day, 2.2 mg/day, 2.3 mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day,
2.7 mg/day, 2.8 mg/day, 2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2
mg/day, 3.3 mg/day, 3.4 mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day,
3.8 mg/day, 3.9 mg/day, 4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3
mg/day, 4.4 mg/day, 4.5 mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day,
4.9 mg/day, 5.0 mg/day, 5.1 mg/day, 5.2 mg/day, 5.3 mg/day, 5.4
mg/day, 5.5 mg/day, 5.6 mg/day, 5.7 mg/day, 5.8 mg/day, 5.9 mg/day,
6.0 mg/day, 6.1 mg/day, 6.2 mg/day, 6.3 mg/day, 6.4 mg/day, 6.5
mg/day, 6.6 mg/day, 6.7 mg/day, 6.8 mg/day, 6.9 mg/day, 7.0 mg/day,
7.1 mg/day, 7.2 mg/day, 7.3 mg/day, 7.4 mg/day, 7.5 mg/day, 7.6
mg/day, 7.7 mg/day, 7.8 mg/day, 7.9 mg/day, 8.0 mg/day, 8.1 mg/day,
8.2 mg/day, 8.3 mg/day, 8.4 mg/day, 8.5 mg/day, 8.6 mg/day, 8.7
mg/day, 8.8 mg/day, 8.9 mg/day, 9.0 mg/day, 9.1 mg/day, 9.2 mg/day,
9.3 mg/day, 9.4 mg/day, 9.5 mg/day, 9.6 mg/day, 9.7 mg/day, 9.8
mg/day, 9.9 mg/day, or 10.0 mg/day, for instance, by oral
administration. In some embodiments, the medroxyprogesterone is
administered to the patient at a dose of 5.0 mg/day, for instance,
by oral administration. In some embodiments, the
medroxyprogesterone is administered to the patient at a dose of 2.5
mg/day, for instance, by oral administration. In some embodiments,
the medroxyprogesterone is administered to the patient at a dose of
1.5 mg/day, for instance, by oral administration.
[0215] In some embodiments, the progestin is drospirenone. The
drospirenone may be administered to the patient, for example, at a
dose of from about 0.1 mg to about 1.0 mg, such as at a dose of
about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8
mg, 0.9 mg, or 1.0 mg, for instance, by oral administration. In
some embodiments, the drospirenone is administered to the patient
at a dose of 0.5 mg, for instance, by oral administration. In some
embodiments, the drospirenone is administered to the patient at a
dose of 0.25 mg, for instance, by oral administration.
[0216] The drospirenone may be administered to the patient one or
more times per day, week, or month. The drospirenone may be
administered to the patient, for example, at a dose of from about
0.1 mg/day to about 1.0 mg/day, such as at a dose of about 0.1
mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day,
0.7 mg/day, 0.8 mg/day, 0.9 mg/day, or 1.0 mg/day, for instance, by
oral administration. In some embodiments, the drospirenone is
administered to the patient at a dose of 0.5 mg/day, for instance,
by oral administration. In some embodiments, the drospirenone is
administered to the patient at a dose of 0.25 mg/day, for instance,
by oral administration.
[0217] In some embodiments, the add-back therapy includes an
estrogen and a progestin. In some embodiments, the add-back therapy
includes .beta.17-estradiol and norethindrone or a compound that is
metabolized in vivo to produce norethindrone, such as an ester of
norethindrone that is de-esterified in vivo to produce
norethindrone, for instance, norethindrone acetate.
[0218] In some embodiments, the patient does not exhibit a
reduction in BMD of greater than 5% following administration of the
relugolix and the add-back therapy. In some embodiments, the
patient does not exhibit a reduction in BMD of greater than 1%
following administration of the relugolix and the add-back therapy.
The add-back therapy may be formulated for oral administration. For
instance, the add-back therapy may be formulated as a tablet,
capsule, gel cap, powder, liquid solution, or liquid suspension. In
some embodiments, the add-back therapy includes both an estrogen,
such as 617-estradiol, and a progestin, such as norethindrone or
norethindrone acetate. The estrogen and progestin may be
administered separately or admixed in a single composition, such as
a single tablet, capsule, gel cap, powder, liquid solution, or
liquid suspension.
[0219] In some embodiments, the GnRH antagonist is ASP-1707 or a
derivative or variant thereof, such as a compound described in U.S.
Pat. No. 6,960,591; 7,569,688; 7,960,562; or 9,527,818, the
disclosures of which are incorporated herein by reference in their
entirety. In some embodiments, the method includes administering 10
mg/day or more (e.g., from 15 mg/day to 100 mg/day or more, such as
15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day,
45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day,
75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day,
or more) of ASP-1707 to the patient if the concentration of AMH in
the sample isolated from the patient is above the AMH reference
range. In some embodiments, the method includes administering from
15 mg/day to 50 mg/day of ASP-1707 to the patient if the
concentration of AMH in the sample isolated from the patient is
above the AMH reference range.
[0220] In some embodiments, the method includes administering less
than 10 mg/day (e.g., from 5 mg/day to 9 mg/day, such as 5 mg/day,
6 mg/day, 7 mg/day, 8 mg/day, or 9 mg/day) of ASP-1707 to the
patient if the concentration of AMH in the sample isolated from the
patient is below the AMH reference range. In some embodiments, the
method includes administering from 5 mg/day to 7.5 mg/day of
ASP-1707 to the patient if the concentration of AMH in the sample
isolated from the patient is below the AMH reference range.
[0221] In some embodiments, the method includes administering from
7.5 mg/day to 15 mg/day (e.g., 7.5 mg/day, 10 mg/day, 12.5 mg/day,
or 15 mg/day) of ASP-1707 to the patient if the concentration of
AMH in the sample isolated from the patient is within the AMH
reference range. In some embodiments, the method includes
administering 10 mg/day of ASP-1707 to the patient if the
concentration of AMH in the sample isolated from the patient is
within the AMH reference range.
[0222] In some embodiments, the GnRH antagonist is BAY-784 or a
derivative or variant thereof. The GnRH antagonist may be a
compound described in US Patent Application Publication No.
2014/0357655 or 2016/0052936, the disclosures of which are
incorporated herein by reference in their entirety.
[0223] When administered at elevated doses (for instance, doses of
40 mg/day or more) ASP-1707 and/or BAY-784 may be administered in
combination with add-back therapy. The add-back therapy may be
administered to the patient concurrently with the GnRH antagonist,
prior to administration of the GnRH antagonist, or following
administration of the GnRH antagonist.
[0224] In some embodiments, the add-back therapy includes an
estrogen. In some embodiments, the estrogen is selected from the
group consisting of .beta.17-estradiol, ethinyl estradiol, and
conjugated estrogens, such as conjugated equine estrogens.
[0225] In some embodiments, the estrogen is .beta.17-estradiol. The
.beta.17-estradiol may be administered to the patient, for example,
at a dose of from about 0.1 mg to about 2.5 mg, such as at a dose
of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg,
0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6
mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg,
or 2.5 mg, for instance, by oral administration. In some
embodiments, the .beta.17-estradiol is administered to the patient
at a dose of 1.0 mg, for instance, by oral administration. In some
embodiments, the .beta.17-estradiol is administered to the patient
at a dose of 0.5 mg, for instance, by oral administration.
[0226] The .beta.17-estradiol may be administered to the patient
one or more times per day, week, or month. The .beta.17-estradiol
may be administered to the patient, for example, at a dose of from
about 0.1 mg/day to about 2.5 mg/day, such as at a dose of about
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6
mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day,
1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7
mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2 mg/day,
2.3 mg/day, 2.4 mg/day, or 2.5 mg/day, for instance, by oral
administration. In some embodiments, the .beta.17-estradiol is
administered to the patient ata dose of 1.0 mg/day, for instance,
by oral administration. In some embodiments, the .beta.17-estradiol
is administered to the patient at a dose of 0.5 mg/day, for
instance, by oral administration.
[0227] In some embodiments, the estrogen is ethinyl estradiol. The
ethinyl estradiol may be administered to the patient, for example,
at a dose of from about 1.0 .mu.g to about 6.0 .mu.g, such as at a
dose of about 1.0 .mu.g, 1.1 .mu.g, 1.2 .mu.g, 1.3 .mu.g, 1.4
.mu.g, 1.5 .mu.g, 1.6 .mu.g, 1.7 .mu.g, 1.8 .mu.g, 1.9 .mu.g, 2.0
.mu.g, 2.1 .mu.g, 2.2 .mu.g, 2.3 .mu.g, 2.4 .mu.g, 2.5 .mu.g, 2.6
.mu.g, 2.7 .mu.g, 2.8 .mu.g, 2.9 .mu.g, 3.0 .mu.g, 3.1 .mu.g, 3.2
.mu.g, 3.3 .mu.g, 3.4 .mu.g, 3.5 .mu.g, 3.6 .mu.g, 3.7 .mu.g, 3.8
.mu.g, 3.9 .mu.g, 4.0 .mu.g, 4.1 .mu.g, 4.2 .mu.g, 4.2 .mu.g, 4.3
.mu.g, 4.4 .mu.g, 4.5 .mu.g, 4.6 .mu.g, 4.7 .mu.g, 4.8 .mu.g, 4.9
.mu.g, 5.0 .mu.g, 5.1 .mu.g, 5.2 .mu.g, 5.3 .mu.g, 5.4 .mu.g, 5.5
.mu.g, 5.6 .mu.g, 5.7 .mu.g, 5.8 .mu.g, 5.9 .mu.g, or 6.0 .mu.g,
for instance, by oral administration. In some embodiments, the
ethinyl estradiol is administered to the patient at a dose of 5.0
.mu.g, for instance, by oral administration. In some embodiments,
the ethinyl estradiol is administered to the patient at a dose of
2.5 .mu.g, for instance, by oral administration.
[0228] The ethinyl estradiol may be administered to the patient one
or more times per day, week, or month. The ethinyl estradiol may be
administered to the patient, for example, at a dose of from about
1.0 .mu.g/day to about 6.0 .mu.g/day, such as at a dose of about
1.0 .mu.g/day, 1.1 .mu.g/day, 1.2 .mu.g/day, 1.3 .mu.g/day, 1.4
.mu.g/day, 1.5 .mu.g/day, 1.6 .mu.g/day, 1.7 .mu.g/day, 1.8
.mu.g/day, 1.9 .mu.g/day, 2.0 .mu.g/day, 2.1 .mu.g/day, 2.2
.mu.g/day, 2.3 .mu.g/day, 2.4 .mu.g/day, 2.5 .mu.g/day, 2.6
.mu.g/day, 2.7 .mu.g/day, 2.8 .mu.g/day, 2.9 .mu.g/day, 3.0
.mu.g/day, 3.1 .mu.g/day, 3.2 .mu.g/day, 3.3 .mu.g/day, 3.4
.mu.g/day, 3.5 .mu.g/day, 3.6 .mu.g/day, 3.7 .mu.g/day, 3.8
.mu.g/day, 3.9 .mu.g/day, 4.0 .mu.g/day, 4.1 .mu.g/day, 4.2
.mu.g/day, 4.2 .mu.g/day, 4.3 .mu.g/day, 4.4 .mu.g/day, 4.5
.mu.g/day, 4.6 .mu.g/day, 4.7 .mu.g/day, 4.8 .mu.g/day, 4.9
.mu.g/day, 5.0 .mu.g/day, 5.1 .mu.g/day, 5.2 .mu.g/day, 5.3
.mu.g/day, 5.4 .mu.g/day, 5.5 .mu.g/day, 5.6 .mu.g/day, 5.7
.mu.g/day, 5.8 .mu.g/day, 5.9 .mu.g/day, or 6.0 .mu.g/day, for
instance, by oral administration. In some embodiments, the ethinyl
estradiol is administered to the patient at a dose of 5.0
.mu.g/day, for instance, by oral administration. In some
embodiments, the ethinyl estradiol is administered to the patient
at a dose of 2.5 .mu.g/day, for instance, by oral
administration.
[0229] In some embodiments, the estrogen is a conjugated estrogen,
such as a conjugated equine estrogen. The conjugated estrogen may
be administered to the patient, for example, at a dose of from
about 0.1 mg to about 2.0 mg, such as at a dose of about 0.1 mg,
0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0
mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg,
1.9 mg, or 2.0 mg, for instance, by oral administration. In some
embodiments, the conjugated estrogen is administered to the patient
at a dose of 0.625 mg, for instance, by oral administration. In
some embodiments, the conjugated estrogen is administered to the
patient at a dose of 0.45 mg, for instance, by oral administration.
In some embodiments, the conjugated estrogen is administered to the
patient at a dose of 0.3 mg, for instance, by oral
administration.
[0230] The conjugated estrogen may be administered to the patient
one or more times per day, week, or month. The conjugated estrogen
may be administered to the patient, for example, at a dose of from
about 0.1 mg/day to about 2.0 mg/day, such as at a dose of about
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6
mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day,
1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7
mg/day, 1.8 mg/day, 1.9 mg/day, or 2.0 mg/day, for instance, by
oral administration. In some embodiments, the conjugated estrogen
is administered to the patient at a dose of 0.625 mg/day, for
instance, by oral administration. In some embodiments, the
conjugated estrogen is administered to the patient at a dose of
0.45 mg/day, for instance, by oral administration. In some
embodiments, the conjugated estrogen is administered to the patient
at a dose of 0.3 mg/day, for instance, by oral administration.
[0231] In some embodiments, the add-back therapy includes a
progestin. In some embodiments, the progestin is selected from the
group consisting of norethindrone or an ester thereof, such as
norethindrone acetate, or another agent such as progesterone,
norgestimate, medroxyprogesterone, or drospirenone.
[0232] In some embodiments, the progestin is norethindrone or a
compound that is metabolized in vivo to produce norethindrone, such
as an ester of norethindrone that is de-esterified in vivo to
produce norethindrone, for instance, norethindrone acetate.
[0233] In some embodiments, the progestin is norethindrone. The
norethindrone may be administered to the patient, for example, at a
dose of from about 0.05 mg to about 5.0 mg, such as at a dose of
about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg,
0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1
mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg,
2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8
mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg,
3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5
mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 1.0 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 0.5 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 0.1 mg, for instance, by
oral administration.
[0234] The norethindrone may be administered to the patient one or
more times per day, week, or month. The norethindrone may be
administered to the patient, for example, at a dose of from about
0.05 mg/day to about 5.0 mg/day, such as at a dose of about 0.05
mg/day, 0.06 mg/day, 0.07 mg/day, 0.08 mg/day, 0.09 mg/day, 0.1
mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day,
0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day, 1.2
mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7 mg/day,
1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2 mg/day, 2.3
mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day, 2.7 mg/day, 2.8 mg/day,
2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2 mg/day, 3.3 mg/day, 3.4
mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day, 3.8 mg/day, 3.9 mg/day,
4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3 mg/day, 4.4 mg/day, 4.5
mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day, 4.9 mg/day, or 5.0
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 1.0
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 0.5
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 0.1
mg/day, for instance, by oral administration.
[0235] In some embodiments, the progestin is norethindrone acetate.
The norethindrone acetate may be administered to the patient, for
example, at a dose of from about 0.05 mg to about 5.0 mg, such as
at a dose of about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1
mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg,
1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8
mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg,
2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5
mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg,
4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, for
instance, by oral administration. In some embodiments, the
norethindrone acetate is administered to the patient at a dose of
1.0 mg/day, for instance, by oral administration. In some
embodiments, the norethindrone acetate is administered to the
patient at a dose of 0.5 mg, for instance, by oral administration.
In some embodiments, the norethindrone acetate is administered to
the patient at a dose of 0.1 mg, for instance, by oral
administration.
[0236] The norethindrone acetate may be administered to the patient
one or more times per day, week, or month. The norethindrone
acetate may be administered to the patient, for example, at a dose
of from about 0.05 mg/day to about 5.0 mg/day, such as at a dose of
about 0.05 mg/day, 0.06 mg/day, 0.07 mg/day, 0.08 mg/day, 0.09
mg/day, 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day,
0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1
mg/day, 1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day,
1.7 mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2
mg/day, 2.3 mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day, 2.7 mg/day,
2.8 mg/day, 2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2 mg/day, 3.3
mg/day, 3.4 mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day, 3.8 mg/day,
3.9 mg/day, 4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3 mg/day, 4.4
mg/day, 4.5 mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day, 4.9 mg/day,
or 5.0 mg/day, for instance, by oral administration. In some
embodiments, the norethindrone acetate is administered to the
patient at a dose of 1.0 mg/day, for instance, by oral
administration. In some embodiments, the norethindrone acetate is
administered to the patient at a dose of 0.5 mg/day, for instance,
by oral administration. In some embodiments, the norethindrone
acetate is administered to the patient at a dose of 0.1 mg/day, for
instance, by oral administration.
[0237] In some embodiments, the progestin is progesterone. The
progesterone may be administered to the patient, for example, at a
dose of from about 50 mg to about 250 mg, such as a dose of about
50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95
mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg,
140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180
mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg,
225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg, for instance, by
oral administration. In some embodiments, the progesterone is
administered to the patient at a dose of 200 mg, for instance, by
oral administration. In some embodiments, the progesterone is
administered to the patient at a dose of 100 mg, for instance, by
oral administration.
[0238] The progesterone may be administered to the patient one or
more times per day, week, or month. The progesterone may be
administered to the patient, for example, at a dose of from about
50 mg/day to about 250 mg/day, such as a dose of about 50 mg/day,
55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day,
85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110
mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day,
140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, 160 mg/day, 165
mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day, 190 mg/day,
195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, 215 mg/day, 220
mg/day, 225 mg/day, 230 mg/day, 235 mg/day, 240 mg/day, 245 mg/day,
or 250 mg/day, for instance, by oral administration. In some
embodiments, the progesterone is administered to the patient at a
dose of 200 mg/day, for instance, by oral administration. In some
embodiments, the progesterone is administered to the patient at a
dose of 100 mg/day, for instance, by oral administration.
[0239] In some embodiments, the progestin is norgestimate. The
norgestimate may be administered to the patient, for example, at a
dose of from about 0.01 mg to about 2.0 mg, such as at a dose of
about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07
mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6
mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg,
1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg, for instance, by
oral administration. In some embodiments, the norgestimate is
administered to the patient at a dose of 0.09 mg, for instance, by
oral administration.
[0240] The norgestimate may be administered to the patient one or
more times per day, week, or month. The norgestimate may be
administered to the patient, for example, at a dose of from about
0.01 mg/day to about 2.0 mg/day, such as at a dose of about 0.01
mg/day, 0.02 mg/day, 0.03 mg/day, 0.04 mg/day, 0.05 mg/day, 0.06
mg/day, 0.07 mg/day, 0.08 mg/day, 0.09 mg/day, 0.1 mg/day, 0.2
mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day, 0.7 mg/day,
0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day, 1.2 mg/day, 1.3
mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7 mg/day, 1.8 mg/day,
1.9 mg/day, or 2.0 mg/day, for instance, by oral administration. In
some embodiments, the norgestimate is administered to the patient
at a dose of 0.09 mg/day, for instance, by oral administration.
[0241] In some embodiments, the progestin is medroxyprogesterone.
The medroxyprogesterone may be administered to the patient, for
example, at a dose of from about 0.5 mg to about 10.0 mg, such as
at a dose of about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg,
1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9
mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg,
2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6
mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg,
4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3
mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6.0 mg, 6.1 mg,
6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0
mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg,
7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7
mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg,
9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg, for instance, by oral
administration. In some embodiments, the medroxyprogesterone is
administered to the patient at a dose of 5.0 mg, for instance, by
oral administration. In some embodiments, the medroxyprogesterone
is administered to the patient at a dose of 2.5 mg, for instance,
by oral administration. In some embodiments, the
medroxyprogesterone is administered to the patient at a dose of 1.5
mg, for instance, by oral administration.
[0242] The medroxyprogesterone may be administered to the patient
one or more times per day, week, or month. The medroxyprogesterone
may be administered to the patient, for example, at a dose of from
about 0.5 mg/day to about 10.0 mg/day, such as at a dose of about
0.5 mg/day, 0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0
mg/day, 1.1 mg/day, 1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day,
1.6 mg/day, 1.7 mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1
mg/day, 2.2 mg/day, 2.3 mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day,
2.7 mg/day, 2.8 mg/day, 2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2
mg/day, 3.3 mg/day, 3.4 mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day,
3.8 mg/day, 3.9 mg/day, 4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3
mg/day, 4.4 mg/day, 4.5 mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day,
4.9 mg/day, 5.0 mg/day, 5.1 mg/day, 5.2 mg/day, 5.3 mg/day, 5.4
mg/day, 5.5 mg/day, 5.6 mg/day, 5.7 mg/day, 5.8 mg/day, 5.9 mg/day,
6.0 mg/day, 6.1 mg/day, 6.2 mg/day, 6.3 mg/day, 6.4 mg/day, 6.5
mg/day, 6.6 mg/day, 6.7 mg/day, 6.8 mg/day, 6.9 mg/day, 7.0 mg/day,
7.1 mg/day, 7.2 mg/day, 7.3 mg/day, 7.4 mg/day, 7.5 mg/day, 7.6
mg/day, 7.7 mg/day, 7.8 mg/day, 7.9 mg/day, 8.0 mg/day, 8.1 mg/day,
8.2 mg/day, 8.3 mg/day, 8.4 mg/day, 8.5 mg/day, 8.6 mg/day, 8.7
mg/day, 8.8 mg/day, 8.9 mg/day, 9.0 mg/day, 9.1 mg/day, 9.2 mg/day,
9.3 mg/day, 9.4 mg/day, 9.5 mg/day, 9.6 mg/day, 9.7 mg/day, 9.8
mg/day, 9.9 mg/day, or 10.0 mg/day, for instance, by oral
administration. In some embodiments, the medroxyprogesterone is
administered to the patient at a dose of 5.0 mg/day, for instance,
by oral administration. In some embodiments, the
medroxyprogesterone is administered to the patient at a dose of 2.5
mg/day, for instance, by oral administration. In some embodiments,
the medroxyprogesterone is administered to the patient at a dose of
1.5 mg/day, for instance, by oral administration.
[0243] In some embodiments, the progestin is drospirenone. The
drospirenone may be administered to the patient, for example, at a
dose of from about 0.1 mg to about 1.0 mg, such as ata dose of
about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8
mg, 0.9 mg, or 1.0 mg, for instance, by oral administration. In
some embodiments, the drospirenone is administered to the patient
at a dose of 0.5 mg, for instance, by oral administration. In some
embodiments, the drospirenone is administered to the patient at a
dose of 0.25 mg, for instance, by oral administration.
[0244] The drospirenone may be administered to the patient one or
more times per day, week, or month. The drospirenone may be
administered to the patient, for example, at a dose of from about
0.1 mg/day to about 1.0 mg/day, such as at a dose of about 0.1
mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day,
0.7 mg/day, 0.8 mg/day, 0.9 mg/day, or 1.0 mg/day, for instance, by
oral administration. In some embodiments, the drospirenone is
administered to the patient at a dose of 0.5 mg/day, for instance,
by oral administration. In some embodiments, the drospirenone is
administered to the patient at a dose of 0.25 mg/day, for instance,
by oral administration.
[0245] In some embodiments, the add-back therapy includes an
estrogen and a progestin. In some embodiments, the add-back therapy
includes .beta.17-estradiol and norethindrone or a compound that is
metabolized in vivo to produce norethindrone, such as an ester of
norethindrone that is de-esterified in vivo to produce
norethindrone, for instance, norethindrone acetate.
[0246] In some embodiments, the patient does not exhibit a
reduction in BMD of greater than 5% following administration of the
ASP-1707 or BAY-784 and the add-back therapy. In some embodiments,
the patient does not exhibit a reduction in BMD of greater than 1%
following administration of the ASP-1707 or BAY-784 and the
add-back therapy. The add-back therapy may be formulated for oral
administration. For instance, the add-back therapy may be
formulated as a tablet, capsule, gel cap, powder, liquid solution,
or liquid suspension. In some embodiments, the add-back therapy
includes both an estrogen, such as .beta.17-estradiol, and a
progestin, such as norethindrone or norethindrone acetate. The
estrogen and progestin may be administered separately or admixed in
a single composition, such as a single tablet, capsule, gel cap,
powder, liquid solution, or liquid suspension.
[0247] In some embodiments, the method includes orally
administering the GnRH antagonist to the patient. In some
embodiments, the method includes intravenously administering the
GnRH antagonist to the patient.
[0248] In another aspect, the invention features a kit that
contains the GnRH antagonist of any of the above aspects or
embodiments of the invention. The kit may further contain one or
more agents capable of detecting AMH and/or a package insert. The
package insert may instruct a user of the kit to perform the method
of any one of the above aspects or embodiments of the
invention.
[0249] In some embodiments, the kit includes one or more agents
capable of detecting a compound selected from the group consisting
of E2, LH, and FSH. In some embodiments, the kit includes a
thienopyrimidine GnRH antagonist, such as a compound represented by
formula (II) or the choline salt thereof. In some embodiments, the
kit includes a GnRH antagonist selected from the group consisting
of elagolix, relugolix, ASP-1707, SKI2670, and BAY-784, or a
derivative or variant thereof.
[0250] In another aspect, the invention features a method of
treating endometriosis in a patient (e.g., a female human patient,
such as a premenopausal female human patient). In another aspect,
the invention features a method of reducing the concentration of
E2, follicle-stimulating hormone (FSH), and/or luteinizing hormone
(LH) in the blood of a patient (e.g., a female human patient, such
as a premenopausal female human patient). In another aspect, the
invention features a method of reducing pain (e.g.,
endometriosis-associated pain) in a patient (e.g., a female human
patient, such as a premenopausal female human patient).
[0251] In any of the preceding aspects of the invention, the method
may include the step of determining the concentration of E2 in a
sample (e.g., a blood sample) isolated from the patient. In some
embodiments, the concentration of E2 in a sample (e.g., a blood
sample) isolated from the patient has previously been determined.
The method may include: [0252] a. comparing the concentration of E2
to an E2 reference range; and [0253] b. administering an increased
dose of the GnRH antagonist to the patient if the concentration of
E2 in the sample isolated from the patient is above the E2
reference range, or administering a decreased dose of the GnRH
antagonist to the patient if the concentration of E2 in the sample
isolated from the patient is below the E2 reference range.
[0254] In some embodiments, the method includes administering the
originally dispensed dose of the GnRH antagonist to the patient if
the concentration of E2 in the sample isolated from the patient is
within the E2 reference range.
[0255] In some embodiments, the originally dispensed dose of the
GnRH antagonist is from 10 to 500 mg/day (e.g., 10 mg/day, 15
mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 45
mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75
mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105
mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day,
135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, 160
mg/day, 165 mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day,
190 mg/day, 195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, 215
mg/day, 220 mg/day, 225 mg/day, 230 mg/day, 235 mg/day, 240 mg/day,
245 mg/day, 250 mg/day, 255 mg/day, 260 mg/day, 265 mg/day, 270
mg/day, 275 mg/day, 280 mg/day, 285 mg/day, 290 mg/day, 295 mg/day,
300 mg/day, 305 mg/day, 310 mg/day, 315 mg/day, 320 mg/day, 325
mg/day, 330 mg/day, 335 mg/day, 340 mg/day, 345 mg/day, 350 mg/day,
355 mg/day, 360 mg/day, 365 mg/day, 370 mg/day, 375 mg/day, 380
mg/day, 385 mg/day, 390 mg/day, 395 mg/day, 400 mg/day, 405 mg/day,
410 mg/day, 415 mg/day, 420 mg/day, 425 mg/day, 430 mg/day, 435
mg/day, 440 mg/day, 445 mg/day, 450 mg/day, 455 mg/day, 460 mg/day,
465 mg/day, 470 mg/day, 475 mg/day, 480 mg/day, 485 mg/day, 490
mg/day, 495 mg/day, or 500 mg/day).
[0256] For instance, in some embodiments, the originally dispensed
dose of the GnRH antagonist is 50 mg/day, 75 mg/day, 100 mg/day, or
200 mg/day and the GnRH antagonist is a compound represented by
formula (I), such as a compound represented by formula (II) or the
choline salt thereof.
[0257] In some embodiments, the originally dispensed dose of the
GnRH antagonist is 150 mg/day and the GnRH antagonist is elagolix
or a derivative or variant thereof, such as a compound described in
U.S. Pat. No. 7,056,927; 7,176,211; 7,419,983; 8,765,948; or
9,382,214; or in US Patent Application Publication No. 2014/0288031
or 2017/0056403, the disclosures of which are incorporated herein
by reference in their entirety. In some embodiments, the originally
dispensed dose of the GnRH antagonist is 400 mg/day and the GnRH
antagonist is elagolix or a derivative or variant thereof, such as
a compound described in U.S. Pat. No. 7,056,927; 7,176,211;
7,419,983; 8,765,948; or 9,382,214; or in US Patent Application
Publication No. 2014/0288031 or 2017/0056403, the disclosures of
which are incorporated herein by reference in their entirety.
[0258] In some embodiments, the originally dispensed dose of the
GnRH antagonist is 40 mg/day and the GnRH antagonist is relugolix
or a derivative or variant thereof, such as a compound described in
U.S. Pat. No. 7,300,935; 8,058,280; 8,735,401; or 9,346,822; or in
US Patent Application Publication No. 2015/0266891, the disclosures
of which are incorporated herein by reference in their
entirety.
[0259] In some embodiments, the originally dispensed dose of the
GnRH antagonist is 10 mg/day and the GnRH antagonist is ASP-1707 or
a derivative or variant thereof, such as a compound described in
U.S. Pat. No. 6,960,591; 7,569,688; 7,960,562; or 9,527,818, the
disclosures of which are incorporated herein by reference in their
entirety.
[0260] In another aspect, the invention provides a method of
optimizing a dosing regimen for the treatment of endometriosis in a
patient (e.g., a female human patient, such as a premenopausal
female human patient) that is undergoing therapy with a GnRH
antagonist. In another aspect, the invention provides a method of
optimizing a dosing regimen for reducing the concentration of E2,
follicle-stimulating hormone (FSH), and/or luteinizing hormone (LH)
in the blood of a patient (e.g., a female human patient, such as a
premenopausal female human patient) that is undergoing therapy with
a GnRH antagonist. In another aspect, the invention provides a
method of optimizing a dosing regimen for reducing pain (e.g.,
endometriosis-associated pain) in a patient (e.g., a female human
patient, such as a premenopausal female human patient) that is
undergoing therapy with a GnRH antagonist.
[0261] In any of the above aspects of the invention, the method may
include the step of determining the concentration of E2 in a sample
(e.g., a blood sample) isolated from the patient. In some
embodiments, the concentration of E2 in a sample (e.g., a blood
sample) isolated from the patient has previously been determined.
The method may include: [0262] a. comparing the concentration of E2
to an E2 reference range; [0263] b. determining that the patient be
administered an increased dose of a GnRH antagonist if the
concentration of E2 in the sample isolated from the patient is
above the E2 reference range, determining that the patient be
administered a decreased dose of a GnRH antagonist if the
concentration of E2 in the sample isolated from the patient is
below the E2 reference range, or determining that the patient be
administered the originally dispensed dose of the GnRH antagonist
if the E2 concentration in the sample isolated from the patient is
within the E2 reference range; and optionally [0264] c.
administering the GnRH antagonist to the patient at the dose
determined in (b).
[0265] In some embodiments, the sample has been isolated from the
patient between about 4 and about 36 weeks (e.g., about 4 weeks, 5
weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12
weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks,
19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25
weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks,
32 weeks, 33 weeks, 34 weeks, 35 weeks, or 36 week) following the
start of the GnRH antagonist therapy. In some embodiments, the
sample was isolated from the patient about 4 weeks following the
start of the GnRH antagonist therapy. In some embodiments, the
sample was isolated from the patient about 8 weeks following the
start of the GnRH antagonist therapy. In some embodiments, the
sample was isolated from the patient about 12 weeks following the
start of GnRH antagonist therapy. In some embodiments, the sample
was isolated from the patient about 24 weeks following the start of
the GnRH antagonist therapy.
[0266] In some embodiments, the patient is administered the
newly-determined dose of the GnRH antagonist between about 4 and
about 36 weeks (e.g., about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8
weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks,
15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21
weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks,
28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34
weeks, 35 weeks, or 36 week) following the start of the GnRH
antagonist therapy. For example, the sample may be isolated from
the patient about 4 weeks following the inception of the GnRH
antagonist therapy, and the concentration of E2 in the sample can
subsequently be compared to the E2 reference range to determine an
appropriate GnRH dosage as described herein, and the patient may
then be administered the newly-determined GnRH dosage either at
about 4 weeks following the start of the GnRH antagonist therapy or
at a later date, such as at about 12 weeks following the start of
GnRH antagonist therapy. In some embodiments, the patient is
administered the newly-determined GnRH antagonist dosage about 24
weeks following the inception of the GnRH antagonist therapy. In
some embodiments, the sample is isolated from the patient about 8
weeks following the inception of the GnRH antagonist therapy, and
the concentration of E2 in the sample is compared to the E2
reference range to determine an appropriate GnRH dosage as
described herein. The patient may then be administered the
newly-determined GnRH dosage either at about 8 weeks following the
start of the GnRH antagonist therapy or at a later date, such as at
about 12 weeks following the start of GnRH antagonist therapy. In
some embodiments, the patient is administered the newly-determined
GnRH antagonist dosage about 24 weeks following the inception of
the GnRH antagonist therapy.
[0267] In some embodiments, the E2 reference range is from 20 to 50
pg/ml. Thus, it will be appreciated that an E2 concentration of
less than 20 pg/ml (e.g., 1 pg/ml, 2 pg/ml, 3 pg/ml, 4 pg/ml, 5
pg/ml, 6 pg/ml, 7 pg/ml, 8 pg/ml, 9 pg/ml, 10 pg/ml, 11 pg/ml, 12
pg/ml, 13 pg/ml, 14 pg/ml, 15 pg/ml, 16 pg/ml, 17 pg/ml, 18 pg/ml,
or 19 pg/ml) is considered below an E2 reference range of from 20
to 50 pg/ml. Likewise, an E2 concentration of greater than 50 pg/ml
(e.g., 51 pg/ml, 52 pg/ml, 53 pg/ml, 54 pg/ml, 55 pg/ml, 60 pg/ml,
75 pg/ml, or greater) is considered above an E2 reference range of
from 20 to 50 pg/ml.
[0268] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to reduce or
alleviate a symptom of the endometriosis, such as
endometriosis-associated pain.
[0269] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to reduce
the serum concentration of E2 in the patient to between about 20
and about 50 pg/ml (e.g., to about 20 pg/ml, 25 pg/ml, 30 pg/ml, 35
pg/ml, 40 pg/ml, 45 pg/ml, or 50 pg/ml). In some embodiments, the
serum concentration of E2 is reduced to between about 20 and about
50 pg/ml within about 4 to about 36 weeks of administering the GnRH
antagonist to the patient (e.g., within about 4 weeks, 5 weeks, 6
weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13
weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks,
20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26
weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks,
33 weeks, 34 weeks, 35 weeks, or 36 weeks of administering the GnRH
antagonist to the patient). In some embodiments, the serum
concentration of E2 is reduced to between about 20 and about 50
pg/ml within about 4 weeks of administering the GnRH antagonist to
the patient. In some embodiments, the serum concentration of E2 is
reduced to between about 20 and about 50 pg/ml within about 12
weeks of administering the GnRH antagonist to the patient. In some
embodiments, the serum concentration of E2 is reduced to between
about 20 and about 50 pg/ml within about 24 weeks of administering
the GnRH antagonist to the patient.
[0270] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to reduce
the serum concentration of follicle stimulating hormone (FSH) in
the patient to between about 0.1 and about 10 mIU/ml (e.g., to
about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5,
6, 7, 8, 9, or 10 mIU/ml). In some embodiments, the serum
concentration of FSH is reduced to between about 0.1 and about 10
mIU/mL within about 4 to about 36 weeks of administering the GnRH
antagonist to the patient (e.g., within about 4 weeks, 5 weeks, 6
weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13
weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks,
20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26
weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks,
33 weeks, 34 weeks, 35 weeks, or 36 weeks of administering the GnRH
antagonist to the patient). In some embodiments, the serum
concentration of FSH is reduced to between about 0.1 and about 10
mIU/mL within about 4 weeks of administering the GnRH antagonist to
the patient. In some embodiments, the serum concentration of FSH is
reduced to between about 0.1 and about 10 mIU/mL within about 12
weeks of administering the GnRH antagonist to the patient. In some
embodiments, the serum concentration of FSH is reduced to between
about 0.1 and about 10 mIU/mL within about 24 weeks of
administering the GnRH antagonist to the patient.
[0271] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to reduce
the serum concentration of luteinizing hormone (LH) in the patient
to between about 0.1 and about 10 mIU/ml (e.g., to about 0.1, 0.2,
0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
mIU/ml). In some embodiments, the serum concentration of LH is
reduced to between about 0.1 and about 10 mIU/mL within about 4 to
about 36 weeks of administering the GnRH antagonist to the patient
(e.g., within about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9
weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks,
16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22
weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks,
29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35
weeks, or 36 weeks of administering the GnRH antagonist to the
patient). In some embodiments, the serum concentration of LH is
reduced to between about 0.1 and about 10 mIU/mL within about 4
weeks of administering the GnRH antagonist to the patient. In some
embodiments, the serum concentration of LH is reduced to between
about 0.1 and about 10 mIU/mL within about 12 weeks of
administering the GnRH antagonist to the patient. In some
embodiments, the serum concentration of LH is reduced to between
about 0.1 and about 10 mIU/mL within about 24 weeks of
administering the GnRH antagonist to the patient.
[0272] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to reduce
endometriosis-associated pain experienced by the patient. In some
embodiments, the endometriosis-associated pain is reduced within
about 4 to about 36 weeks of administering the GnRH antagonist to
the patient (e.g., within about 4 weeks, 5 weeks, 6 weeks, 7 weeks,
8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks,
15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21
weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks,
28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34
weeks, 35 weeks, or 36 weeks of administering the GnRH antagonist
to the patient). In some embodiments, the endometriosis-associated
pain is reduced within about 4 weeks of administering the GnRH
antagonist to the patient. In some embodiments, the
endometriosis-associated pain is reduced within about 12 weeks of
administering the GnRH antagonist to the patient. In some
embodiments, the endometriosis-associated pain is reduced within
about 24 weeks of administering the GnRH antagonist to the patient.
In some embodiments, the endometriosis-associated pain is selected
from the group consisting of pelvic pain, dyspareunia, and
dyschezia.
[0273] In some embodiments, the endometriosis-associated pain is
assessed by determining a Numerical Rating Score (NRS) for the
patient. In some embodiments, the NRS is reduced by from about 1%
to about 50% (e.g., by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%). In some
embodiments the NRS is reduced by about 30%.
[0274] In some embodiments, the endometriosis-associated pain is
assessed by determining a Verbal Rating Score (VRS) for the
patient. In some embodiments, the VRS is reduced by from about 1%
to about 50% (e.g., by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%). In some
embodiments the VRS is reduced by about 30%.
[0275] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to alleviate
a symptom selected from the group consisting of dysmenorrhea,
non-menstrual pelvic pain, and dyspareunia. In some embodiments,
the symptom is alleviated within about 4 to about 36 weeks of
administering the GnRH antagonist to the patient (e.g., within
about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10
weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks,
17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23
weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks,
30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, or 36
weeks of administering the GnRH antagonist to the patient). In some
embodiments, the symptom is alleviated within about 4 weeks of
administering the GnRH antagonist to the patient. In some
embodiments, the symptom is alleviated within about 12 weeks of
administering the GnRH antagonist to the patient. In some
embodiments, the symptom is alleviated within about 24 weeks of
administering the GnRH antagonist to the patient.
[0276] In some embodiments, the symptom is assessed by determining
a Biberoglu and Behrman (B&B) scale score for the patient. In
some embodiments, the B&B score is reduced by from about 1% to
about 50% (e.g., by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%).
[0277] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount sufficient to reduce an
Endometriosis Health Profile-5 (EHP-5) score determined for the
patient. In some embodiments, the EHP-5 score is reduced within
about 4 to about 36 weeks of administering the GnRH antagonist to
the patient (e.g., within about 4 weeks, 5 weeks, 6 weeks, 7 weeks,
8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks,
15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21
weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks,
28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34
weeks, 35 weeks, or 36 weeks of administering the GnRH antagonist
to the patient). In some embodiments, the EHP-5 score is reduced
within about 4 weeks of administering the GnRH antagonist to the
patient. In some embodiments, the EHP-5 score is reduced within
about 12 weeks of administering the GnRH antagonist to the patient.
In some embodiments, the EHP-5 score is reduced within about 24
weeks of administering the GnRH antagonist to the patient. In some
embodiments, the EHP-5 score is reduced by from about 1% to about
50% (e.g., by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%,
20%, 25%, 30%, 35%, 40%, 45%, or 50%).
[0278] In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount that does not cause a
reduction in bone mineral density (BMD) in the patient of greater
than 5%. In some embodiments, the method includes administering the
GnRH antagonist to the patient in an amount that does not cause a
reduction in BMD in the patient of greater than 1%.
[0279] In some embodiments, the method includes administering
add-back therapy to the patient. In some embodiments, the add-back
therapy is administered to the patient only if the dosage of the
GnRH antagonist is increased in response to a finding that the E2
concentration in the sample isolated from the patient is greater
than the E2 reference range. In some embodiments, the add-back
therapy is administered to the patient regardless of whether the
dose of the GnRH antagonist is increased, decreased, or remains the
same upon evaluating the concentration of E2 in the sample obtained
from the patient.
[0280] When administered, the add-back therapy may be administered
to the patient concurrently with the GnRH antagonist, prior to
administration of the GnRH antagonist, or following administration
of the GnRH antagonist. In some embodiments, add-back therapy is
administered as a fixed dose combination containing a GnRH
antagonist, estrogen, and one or more additional agents, such as a
progestin, in a single pharmaceutical composition. For instance,
add-back therapy may be administered as a fixed dose combination of
a GnRH antagonist, estrogen (e.g., in the form of E2) and a
progestin (e.g., norethindrone or a compound that is metabolized in
vivo to produce norethindrone, such as an ester of norethindrone
that is de-esterified in vivo to produce norethindrone, for
instance, norethindrone acetate) in the form of a single
pharmaceutical composition, such as a single tablet, capsule, gel
cap, powder, liquid solution, or liquid suspension.
[0281] In some embodiments, the add-back therapy includes an
estrogen. In some embodiments, the estrogen is selected from the
group consisting of .beta.17-estradiol, ethinyl estradiol, and
conjugated estrogens, such as conjugated equine estrogens.
[0282] In some embodiments, the estrogen is .beta.17-estradiol. The
.beta.17-estradiol may be administered to the patient, for example,
at a dose of from about 0.1 mg to about 2.5 mg, such as at a dose
of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg,
0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6
mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg,
or 2.5 mg, for instance, by oral administration. In some
embodiments, the .beta.17-estradiol is administered to the patient
at a dose of 1.0 mg, for instance, by oral administration. In some
embodiments, the .beta.17-estradiol is administered to the patient
at a dose of 0.5 mg, for instance, by oral administration.
[0283] The .beta.17-estradiol may be administered to the patient
one or more times per day, week, or month. The .beta.17-estradiol
may be administered to the patient, for example, at a dose of from
about 0.1 mg/day to about 2.5 mg/day, such as at a dose of about
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6
mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day,
1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7
mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2 mg/day,
2.3 mg/day, 2.4 mg/day, or 2.5 mg/day, for instance, by oral
administration. In some embodiments, the .beta.17-estradiol is
administered to the patient ata dose of 1.0 mg/day, for instance,
by oral administration. In some embodiments, the .beta.17-estradiol
is administered to the patient at a dose of 0.5 mg/day, for
instance, by oral administration.
[0284] In some embodiments, the estrogen is ethinyl estradiol. The
ethinyl estradiol may be administered to the patient, for example,
at a dose of from about 1.0 .mu.g to about 6.0 .mu.g, such as at a
dose of about 1.0 .mu.g, 1.1 .mu.g, 1.2 .mu.g, 1.3 .mu.g, 1.4
.mu.g, 1.5 .mu.g, 1.6 .mu.g, 1.7 .mu.g, 1.8 .mu.g, 1.9 .mu.g, 2.0
.mu.g, 2.1 .mu.g, 2.2 .mu.g, 2.3 .mu.g, 2.4 .mu.g, 2.5 .mu.g, 2.6
.mu.g, 2.7 .mu.g, 2.8 .mu.g, 2.9 .mu.g, 3.0 .mu.g, 3.1 .mu.g, 3.2
.mu.g, 3.3 .mu.g, 3.4 .mu.g, 3.5 .mu.g, 3.6 .mu.g, 3.7 .mu.g, 3.8
.mu.g, 3.9 .mu.g, 4.0 .mu.g, 4.1 .mu.g, 4.2 .mu.g, 4.2 .mu.g, 4.3
.mu.g, 4.4 .mu.g, 4.5 .mu.g, 4.6 .mu.g, 4.7 .mu.g, 4.8 .mu.g, 4.9
.mu.g, 5.0 .mu.g, 5.1 .mu.g, 5.2 .mu.g, 5.3 .mu.g, 5.4 .mu.g, 5.5
.mu.g, 5.6 .mu.g, 5.7 .mu.g, 5.8 .mu.g, 5.9 .mu.g, or 6.0 .mu.g,
for instance, by oral administration. In some embodiments, the
ethinyl estradiol is administered to the patient at a dose of 5.0
.mu.g, for instance, by oral administration. In some embodiments,
the ethinyl estradiol is administered to the patient at a dose of
2.5 .mu.g, for instance, by oral administration.
[0285] The ethinyl estradiol may be administered to the patient one
or more times per day, week, or month. The ethinyl estradiol may be
administered to the patient, for example, at a dose of from about
1.0 .mu.g/day to about 6.0 .mu.g/day, such as at a dose of about
1.0 .mu.g/day, 1.1 .mu.g/day, 1.2 .mu.g/day, 1.3 .mu.g/day, 1.4
.mu.g/day, 1.5 .mu.g/day, 1.6 .mu.g/day, 1.7 .mu.g/day, 1.8
.mu.g/day, 1.9 .mu.g/day, 2.0 .mu.g/day, 2.1 .mu.g/day, 2.2
.mu.g/day, 2.3 .mu.g/day, 2.4 .mu.g/day, 2.5 .mu.g/day, 2.6
.mu.g/day, 2.7 .mu.g/day, 2.8 .mu.g/day, 2.9 .mu.g/day, 3.0
.mu.g/day, 3.1 .mu.g/day, 3.2 .mu.g/day, 3.3 .mu.g/day, 3.4
.mu.g/day, 3.5 .mu.g/day, 3.6 .mu.g/day, 3.7 .mu.g/day, 3.8
.mu.g/day, 3.9 .mu.g/day, 4.0 .mu.g/day, 4.1 .mu.g/day, 4.2
.mu.g/day, 4.2 .mu.g/day, 4.3 .mu.g/day, 4.4 .mu.g/day, 4.5
.mu.g/day, 4.6 .mu.g/day, 4.7 .mu.g/day, 4.8 .mu.g/day, 4.9
.mu.g/day, 5.0 .mu.g/day, 5.1 .mu.g/day, 5.2 .mu.g/day, 5.3
.mu.g/day, 5.4 .mu.g/day, 5.5 .mu.g/day, 5.6 .mu.g/day, 5.7
.mu.g/day, 5.8 .mu.g/day, 5.9 .mu.g/day, or 6.0 .mu.g/day, for
instance, by oral administration. In some embodiments, the ethinyl
estradiol is administered to the patient at a dose of 5.0
.mu.g/day, for instance, by oral administration. In some
embodiments, the ethinyl estradiol is administered to the patient
at a dose of 2.5 .mu.g/day, for instance, by oral
administration.
[0286] In some embodiments, the estrogen is a conjugated estrogen,
such as a conjugated equine estrogen. The conjugated estrogen may
be administered to the patient, for example, at a dose of from
about 0.1 mg to about 2.0 mg, such as at a dose of about 0.1 mg,
0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0
mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg,
1.9 mg, or 2.0 mg, for instance, by oral administration. In some
embodiments, the conjugated estrogen is administered to the patient
at a dose of 0.625 mg, for instance, by oral administration. In
some embodiments, the conjugated estrogen is administered to the
patient at a dose of 0.45 mg, for instance, by oral administration.
In some embodiments, the conjugated estrogen is administered to the
patient at a dose of 0.3 mg, for instance, by oral
administration.
[0287] The conjugated estrogen may be administered to the patient
one or more times per day, week, or month. The conjugated estrogen
may be administered to the patient, for example, at a dose of from
about 0.1 mg/day to about 2.0 mg/day, such as at a dose of about
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6
mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day,
1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7
mg/day, 1.8 mg/day, 1.9 mg/day, or 2.0 mg/day, for instance, by
oral administration. In some embodiments, the conjugated estrogen
is administered to the patient at a dose of 0.625 mg/day, for
instance, by oral administration. In some embodiments, the
conjugated estrogen is administered to the patient at a dose of
0.45 mg/day, for instance, by oral administration. In some
embodiments, the conjugated estrogen is administered to the patient
at a dose of 0.3 mg/day, for instance, by oral administration.
[0288] In some embodiments, the add-back therapy includes a
progestin. In some embodiments, the progestin is selected from the
group consisting of norethindrone or an ester thereof, such as
norethindrone acetate, or another agent such as progesterone,
norgestimate, medroxyprogesterone, or drospirenone.
[0289] In some embodiments, the progestin is norethindrone or a
compound that is metabolized in vivo to produce norethindrone, such
as an ester of norethindrone that is de-esterified in vivo to
produce norethindrone, for instance, norethindrone acetate.
[0290] In some embodiments, the progestin is norethindrone. The
norethindrone may be administered to the patient, for example, at a
dose of from about 0.05 mg to about 5.0 mg, such as at a dose of
about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg,
0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1
mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg,
2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8
mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg,
3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5
mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 1.0 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 0.5 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 0.1 mg, for instance, by
oral administration.
[0291] The norethindrone may be administered to the patient one or
more times per day, week, or month. The norethindrone may be
administered to the patient, for example, at a dose of from about
0.05 mg/day to about 5.0 mg/day, such as at a dose of about 0.05
mg/day, 0.06 mg/day, 0.07 mg/day, 0.08 mg/day, 0.09 mg/day, 0.1
mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day,
0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day, 1.2
mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7 mg/day,
1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2 mg/day, 2.3
mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day, 2.7 mg/day, 2.8 mg/day,
2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2 mg/day, 3.3 mg/day, 3.4
mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day, 3.8 mg/day, 3.9 mg/day,
4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3 mg/day, 4.4 mg/day, 4.5
mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day, 4.9 mg/day, or 5.0
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 1.0
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 0.5
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 0.1
mg/day, for instance, by oral administration.
[0292] In some embodiments, the progestin is norethindrone acetate.
The norethindrone acetate may be administered to the patient, for
example, at a dose of from about 0.05 mg to about 5.0 mg, such as
at a dose of about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1
mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg,
1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8
mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg,
2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5
mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg,
4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, for
instance, by oral administration. In some embodiments, the
norethindrone acetate is administered to the patient at a dose of
1.0 mg/day, for instance, by oral administration. In some
embodiments, the norethindrone acetate is administered to the
patient at a dose of 0.5 mg, for instance, by oral administration.
In some embodiments, the norethindrone acetate is administered to
the patient at a dose of 0.1 mg, for instance, by oral
administration.
[0293] The norethindrone acetate may be administered to the patient
one or more times per day, week, or month. The norethindrone
acetate may be administered to the patient, for example, at a dose
of from about 0.05 mg/day to about 5.0 mg/day, such as at a dose of
about 0.05 mg/day, 0.06 mg/day, 0.07 mg/day, 0.08 mg/day, 0.09
mg/day, 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day,
0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1
mg/day, 1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day,
1.7 mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2
mg/day, 2.3 mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day, 2.7 mg/day,
2.8 mg/day, 2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2 mg/day, 3.3
mg/day, 3.4 mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day, 3.8 mg/day,
3.9 mg/day, 4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3 mg/day, 4.4
mg/day, 4.5 mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day, 4.9 mg/day,
or 5.0 mg/day, for instance, by oral administration. In some
embodiments, the norethindrone acetate is administered to the
patient at a dose of 1.0 mg/day, for instance, by oral
administration. In some embodiments, the norethindrone acetate is
administered to the patient at a dose of 0.5 mg/day, for instance,
by oral administration. In some embodiments, the norethindrone
acetate is administered to the patient at a dose of 0.1 mg/day, for
instance, by oral administration.
[0294] In some embodiments, the progestin is progesterone. The
progesterone may be administered to the patient, for example, at a
dose of from about 50 mg to about 250 mg, such as a dose of about
50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95
mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg,
140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180
mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg,
225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg, for instance, by
oral administration. In some embodiments, the progesterone is
administered to the patient at a dose of 200 mg, for instance, by
oral administration. In some embodiments, the progesterone is
administered to the patient at a dose of 100 mg, for instance, by
oral administration.
[0295] The progesterone may be administered to the patient one or
more times per day, week, or month. The progesterone may be
administered to the patient, for example, at a dose of from about
50 mg/day to about 250 mg/day, such as a dose of about 50 mg/day,
55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day,
85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110
mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day,
140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, 160 mg/day, 165
mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day, 190 mg/day,
195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, 215 mg/day, 220
mg/day, 225 mg/day, 230 mg/day, 235 mg/day, 240 mg/day, 245 mg/day,
or 250 mg/day, for instance, by oral administration. In some
embodiments, the progesterone is administered to the patient at a
dose of 200 mg/day, for instance, by oral administration. In some
embodiments, the progesterone is administered to the patient at a
dose of 100 mg/day, for instance, by oral administration.
[0296] In some embodiments, the progestin is norgestimate. The
norgestimate may be administered to the patient, for example, at a
dose of from about 0.01 mg to about 2.0 mg, such as at a dose of
about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07
mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6
mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg,
1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg, for instance, by
oral administration. In some embodiments, the norgestimate is
administered to the patient at a dose of 0.09 mg, for instance, by
oral administration.
[0297] The norgestimate may be administered to the patient one or
more times per day, week, or month. The norgestimate may be
administered to the patient, for example, at a dose of from about
0.01 mg/day to about 2.0 mg/day, such as at a dose of about 0.01
mg/day, 0.02 mg/day, 0.03 mg/day, 0.04 mg/day, 0.05 mg/day, 0.06
mg/day, 0.07 mg/day, 0.08 mg/day, 0.09 mg/day, 0.1 mg/day, 0.2
mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day, 0.7 mg/day,
0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day, 1.2 mg/day, 1.3
mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7 mg/day, 1.8 mg/day,
1.9 mg/day, or 2.0 mg/day, for instance, by oral administration. In
some embodiments, the norgestimate is administered to the patient
at a dose of 0.09 mg/day, for instance, by oral administration.
[0298] In some embodiments, the progestin is medroxyprogesterone.
The medroxyprogesterone may be administered to the patient, for
example, at a dose of from about 0.5 mg to about 10.0 mg, such as
at a dose of about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg,
1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9
mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg,
2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6
mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg,
4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3
mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6.0 mg, 6.1 mg,
6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0
mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg,
7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7
mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg,
9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg, for instance, by oral
administration. In some embodiments, the medroxyprogesterone is
administered to the patient at a dose of 5.0 mg, for instance, by
oral administration. In some embodiments, the medroxyprogesterone
is administered to the patient at a dose of 2.5 mg, for instance,
by oral administration. In some embodiments, the
medroxyprogesterone is administered to the patient at a dose of 1.5
mg, for instance, by oral administration.
[0299] The medroxyprogesterone may be administered to the patient
one or more times per day, week, or month. The medroxyprogesterone
may be administered to the patient, for example, at a dose of from
about 0.5 mg/day to about 10.0 mg/day, such as at a dose of about
0.5 mg/day, 0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0
mg/day, 1.1 mg/day, 1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day,
1.6 mg/day, 1.7 mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1
mg/day, 2.2 mg/day, 2.3 mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day,
2.7 mg/day, 2.8 mg/day, 2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2
mg/day, 3.3 mg/day, 3.4 mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day,
3.8 mg/day, 3.9 mg/day, 4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3
mg/day, 4.4 mg/day, 4.5 mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day,
4.9 mg/day, 5.0 mg/day, 5.1 mg/day, 5.2 mg/day, 5.3 mg/day, 5.4
mg/day, 5.5 mg/day, 5.6 mg/day, 5.7 mg/day, 5.8 mg/day, 5.9 mg/day,
6.0 mg/day, 6.1 mg/day, 6.2 mg/day, 6.3 mg/day, 6.4 mg/day, 6.5
mg/day, 6.6 mg/day, 6.7 mg/day, 6.8 mg/day, 6.9 mg/day, 7.0 mg/day,
7.1 mg/day, 7.2 mg/day, 7.3 mg/day, 7.4 mg/day, 7.5 mg/day, 7.6
mg/day, 7.7 mg/day, 7.8 mg/day, 7.9 mg/day, 8.0 mg/day, 8.1 mg/day,
8.2 mg/day, 8.3 mg/day, 8.4 mg/day, 8.5 mg/day, 8.6 mg/day, 8.7
mg/day, 8.8 mg/day, 8.9 mg/day, 9.0 mg/day, 9.1 mg/day, 9.2 mg/day,
9.3 mg/day, 9.4 mg/day, 9.5 mg/day, 9.6 mg/day, 9.7 mg/day, 9.8
mg/day, 9.9 mg/day, or 10.0 mg/day, for instance, by oral
administration. In some embodiments, the medroxyprogesterone is
administered to the patient at a dose of 5.0 mg/day, for instance,
by oral administration. In some embodiments, the
medroxyprogesterone is administered to the patient at a dose of 2.5
mg/day, for instance, by oral administration. In some embodiments,
the medroxyprogesterone is administered to the patient at a dose of
1.5 mg/day, for instance, by oral administration.
[0300] In some embodiments, the progestin is drospirenone. The
drospirenone may be administered to the patient, for example, at a
dose of from about 0.1 mg to about 1.0 mg, such as at a dose of
about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8
mg, 0.9 mg, or 1.0 mg, for instance, by oral administration. In
some embodiments, the drospirenone is administered to the patient
at a dose of 0.5 mg, for instance, by oral administration. In some
embodiments, the drospirenone is administered to the patient at a
dose of 0.25 mg, for instance, by oral administration.
[0301] The drospirenone may be administered to the patient one or
more times per day, week, or month. The drospirenone may be
administered to the patient, for example, at a dose of from about
0.1 mg/day to about 1.0 mg/day, such as at a dose of about 0.1
mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day,
0.7 mg/day, 0.8 mg/day, 0.9 mg/day, or 1.0 mg/day, for instance, by
oral administration. In some embodiments, the drospirenone is
administered to the patient at a dose of 0.5 mg/day, for instance,
by oral administration. In some embodiments, the drospirenone is
administered to the patient at a dose of 0.25 mg/day, for instance,
by oral administration.
[0302] In some embodiments, the add-back therapy includes an
estrogen and a progestin. In some embodiments, the add-back therapy
includes .beta.17-estradiol and norethindrone or a compound that is
metabolized in vivo to produce norethindrone, such as an ester of
norethindrone that is de-esterified in vivo to produce
norethindrone, for instance, norethindrone acetate.
[0303] In some embodiments, the patient does not exhibit a
reduction in BMD of greater than 5% following administration of the
elagolix and the add-back therapy. In some embodiments, the patient
does not exhibit a reduction in BMD of greater than 1% following
administration of the elagolix and the add-back therapy. The
add-back therapy may be formulated for oral administration. For
instance, the add-back therapy may be formulated as a tablet,
capsule, gel cap, powder, liquid solution, or liquid suspension. In
some embodiments, the add-back therapy includes both an estrogen,
such as 617-estradiol, and a progestin, such as norethindrone or
norethindrone acetate. The estrogen and progestin may be
administered separately or admixed in a single composition, such as
a single tablet, capsule, gel cap, powder, liquid solution, or
liquid suspension.
[0304] In some embodiments, the BMD is assessed by dual energy
X-ray absorptiometry. In some embodiments, the BMD is assessed in
the spine or femur of the patient.
[0305] In some embodiments, the GnRH antagonist is a compound
represented by formula (I)
##STR00009##
[0306] wherein ring A is a thiophene ring;
[0307] each R.sup.A is independently a halogen atom, a cyano group,
a nitro group, an optionally substituted lower alkyl group, an
optionally substituted lower alkenyl group, an optionally
substituted lower alkynyl group, a hydroxyiminomethyl group, an
optionally substituted sulfonyl group, an optionally substituted
sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1,
COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3,
CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to
W.sup.3 independently are a hydrogen atom or an optionally
substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind
together with the neighboring nitrogen atom to form an optionally
substituted cyclic amino group;
[0308] m is an integer from 0 to 3;
[0309] ring B is an aryl group or a monocyclic heteroaryl
group;
[0310] each R.sup.B is independently a halogen atom, a cyano group,
an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4,
COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6
independently are a hydrogen atom or an optionally substituted
lower alkyl group, or W.sup.5 and W.sup.6 may bind together with
the neighboring nitrogen atom to form an optionally substituted
cyclic amino group;
[0311] n is an integer from 0 to 2;
[0312] U is a single bond;
[0313] X is a group represented by --S-L-Y, --O-L-Y, --CO-L-Y, or
--SO.sub.2-L-Y, wherein L is an optionally substituted lower
alkylene group;
[0314] Y is a group represented by Z or --NW.sup.7W.sup.8, wherein
W.sup.7 and W.sup.8 independently are a hydrogen atom, an
optionally substituted lower alkyl group, or Z with the proviso
that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or
W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen
atom to form an optionally substituted cyclic amino group;
[0315] Z is an optionally fused and optionally substituted
cycloalkyl group, an optionally fused and optionally substituted
heterocycloalkyl group, an optionally fused and optionally
substituted aryl group, or an optionally fused and optionally
substituted heteroaryl group;
[0316] or a pharmaceutically acceptable salt thereof.
[0317] In some embodiments, the ring A is a thiophene ring
represented by formula (A)
##STR00010##
[0318] In some embodiments, m is 1 or 2. In some embodiments, m is
1. For instance, the ring A may be an optionally substituted
thiophene ring represented by formula (B)
##STR00011##
[0319] Each R.sup.A may independently be, for example, a halogen
atom (e.g., fluorine, chlorine, bromine, or iodine), an optionally
substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3,
wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an
optionally substituted lower alkyl group, or W.sup.2 and W.sup.3
may bind together with the neighboring nitrogen atom to form an
optionally substituted cyclic amino group. In some embodiments,
each R.sup.A is COOH or pharmaceutically acceptable salt
thereof.
[0320] In some embodiments, ring B is an optionally substituted
benzene ring, pyridine ring, or thiophene ring. For instance, ring
B may be represented by a formula selected from the group
consisting of:
##STR00012##
##STR00013##
[0321] In some embodiments, n is 1 or 2. For instance, in some
embodiments, n is 1. Ring B may be, for example, represented by a
formula selected from the group consisting of:
##STR00014##
[0322] In some embodiments, each R.sup.B is independently a halogen
atom, an optionally substituted lower alkyl group, or OW.sup.4,
wherein each W.sup.4 is independently a hydrogen atom or an
optionally substituted lower alkyl group. For instance, each
R.sup.B may be independently a fluorine atom, chlorine atom,
bromine atom, methyl group, or methoxy group.
[0323] In some embodiments, U is a single bond. X may be, for
example, a group represented by --O-L-Y. L may be, for example, a
methylene group. In some embodiments, Y is an optionally
substituted benzene ring represented by formula (C)
##STR00015##
[0324] wherein each R.sup.C is independently a halogen atom, an
optionally substituted lower alkyl group, or OW.sup.9, wherein each
W.sup.9 is independently a hydrogen atom or an optionally
substituted lower alkyl group; and
[0325] p is an integer from 0 to 3.
[0326] In some embodiments, Y is a substituted benzene ring
represented by formula (D)
##STR00016##
[0327] In some embodiments, the compound is represented by formula
(II)
##STR00017##
[0328] or a pharmaceutically acceptable salt thereof.
[0329] In some embodiments, the compound is the choline salt of the
compound represented by formula (II), i.e., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate.
[0330] In some embodiments, the GnRH antagonist includes the
compound represented by formula (II) in a crystalline state. In
some embodiments, the compound exhibits characteristic X-ray powder
diffraction peaks at about 7.1.degree. 2.theta., 11.5.degree.
2.theta., 19.4.degree. 2.theta., 20.3.degree. 2.theta.,
21.5.degree. 2.theta., 22.0.degree. 2.theta., 22.6.degree.
2.theta., 23.5.degree. 2.theta., and 26.2.degree. 2.theta.. In some
embodiments, the compound exhibits .sup.13C solid-state NMR peaks
centered at about 155.8 ppm, 149.8 ppm, 145.3 ppm, 118.0 ppm, 113.7
ppm, 111.6 ppm, 110.3 ppm, 98.1 ppm, 69.8 ppm, 58.7 ppm, 57.1 ppm,
and 55.5 ppm. In some embodiments, the compound exhibits .sup.19F
solid-state NMR peaks centered at about -131.6 ppm, -145.2 ppm, and
-151.8 ppm.
[0331] In some embodiments, the method includes administering from
85 mg/day to 115 mg/day (e.g., 85 mg/day, 90 mg/day, 95 mg/day, 100
mg/day, 105 mg/day, 110 mg/day, or 115 mg/day) or more, such as
from about 185 mg/day to about 215 mg/day (e.g., 185 mg/day, 190
mg/day, 195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, or 215
mg/day) of the compound represented by formula (I), formula (II),
or a pharmaceutically acceptable salt thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to the
patient if the concentration of E2 in the sample isolated from the
patient is within the E2 reference range. In some embodiments, the
method includes administering from 60 to 90 mg/day (e.g., 60
mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, or
90 mg/day) of the compound represented by formula (I), formula
(II), or a pharmaceutically acceptable salt thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to the
patient if the concentration of E2 in the sample isolated from the
patient is within the E2 reference range. In some embodiments, the
method includes administering from 35 to 65 mg/day (e.g., 35
mg/day, 40 mg/day, 45 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60
mg/day, or 65 mg/day) of the compound represented by formula (I),
formula (II), or a pharmaceutically acceptable salt thereof (e.g.,
choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to the
patient if the concentration of E2 in the sample isolated from the
patient is within the E2 reference range.
[0332] In some embodiments, the method includes administering about
100 mg/day or about 200 mg/day of the compound represented by
formula (I), formula (II), or a pharmaceutically acceptable salt
thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to
the patient if the concentration of E2 in the sample isolated from
the patient is within the E2 reference range. In some embodiments,
the method includes administering about 75 mg/day of the compound
represented by formula (I), formula (II), or a pharmaceutically
acceptable salt thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to the
patient if the concentration of E2 in the sample isolated from the
patient is within the E2 reference range. In some embodiments, the
method includes administering about 50 mg/day of the compound
represented by formula (I), formula (II), or a pharmaceutically
acceptable salt thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to
the patient if the concentration of E2 in the sample isolated from
the patient is within the E2 reference range.
[0333] In some embodiments, the method includes administering from
85 mg/day to 115 mg/day (e.g., 85 mg/day, 90 mg/day, 95 mg/day, 100
mg/day, 105 mg/day, 110 mg/day, or 115 mg/day) or more, such as
from about 185 mg/day to about 215 mg/day (e.g., 185 mg/day, 190
mg/day, 195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, or 215
mg/day) of the compound represented by formula (I), formula (II),
or a pharmaceutically acceptable salt thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to the
patient if the concentration of E2 in the sample isolated from the
patient is above the E2 reference range. In some embodiments, the
method includes administering from 60 to 90 mg/day (e.g., 60
mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, or
90 mg/day) of the compound represented by formula (I), formula
(II), or a pharmaceutically acceptable salt thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to the
patient if the concentration of E2 in the sample isolated from the
patient is above the E2 reference range. In some embodiments, the
method includes administering from 35 to 65 mg/day (e.g., 35
mg/day, 40 mg/day, 45 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60
mg/day, or 65 mg/day) of the compound represented by formula (I),
formula (II), or a pharmaceutically acceptable salt thereof (e.g.,
choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to the
patient if the concentration of E2 in the sample isolated from the
patient is above the E2 reference range.
[0334] In some embodiments, the method includes administering about
100 mg/day or about 200 mg/day of the compound represented by
formula (I), formula (II), or a pharmaceutically acceptable salt
thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to
the patient if the concentration of E2 in the sample isolated from
the patient is above the E2 reference range. In some embodiments,
the method includes administering about 75 mg/day of the compound
represented by formula (I), formula (II), or a pharmaceutically
acceptable salt thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to the
patient if the concentration of E2 in the sample isolated from the
patient is above the E2 reference range. In some embodiments, the
method includes administering about 50 mg/day of the compound
represented by formula (I), formula (II), or a pharmaceutically
acceptable salt thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to
the patient if the concentration of E2 in the sample isolated from
the patient is above the E2 reference range.
[0335] In some embodiments, the method includes administering from
85 mg/day to 115 mg/day (e.g., 85 mg/day, 90 mg/day, 95 mg/day, 100
mg/day, 105 mg/day, 110 mg/day, or 115 mg/day) or more, such as
from about 185 mg/day to about 215 mg/day (e.g., 185 mg/day, 190
mg/day, 195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, or 215
mg/day) of the compound represented by formula (I), formula (II),
or a pharmaceutically acceptable salt thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to the
patient if the concentration of E2 in the sample isolated from the
patient is below the E2 reference range. In some embodiments, the
method includes administering from 60 to 90 mg/day (e.g., 60
mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, or
90 mg/day) of the compound represented by formula (I), formula
(II), or a pharmaceutically acceptable salt thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to the
patient if the concentration of E2 in the sample isolated from the
patient is below the E2 reference range. In some embodiments, the
method includes administering from 35 to 65 mg/day (e.g., 35
mg/day, 40 mg/day, 45 mg/day, 45 mg/day, 50 mg/day, 55 mg/day, 60
mg/day, or 65 mg/day) of the compound represented by formula (I),
formula (II), or a pharmaceutically acceptable salt thereof (e.g.,
choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to the
patient if the concentration of E2 in the sample isolated from the
patient is below the E2 reference range.
[0336] In some embodiments, the method includes administering about
100 mg/day or about 200 mg/day of the compound represented by
formula (I), formula (II), or a pharmaceutically acceptable salt
thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to
the patient if the concentration of E2 in the sample isolated from
the patient is below the E2 reference range. In some embodiments,
the method includes administering about 75 mg/day of the compound
represented by formula (I), formula (II), or a pharmaceutically
acceptable salt thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to the
patient if the concentration of E2 in the sample isolated from the
patient is below the E2 reference range. In some embodiments, the
method includes administering about 50 mg/day of the compound
represented by formula (I), formula (II), or a pharmaceutically
acceptable salt thereof (e.g., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate) to
the patient if the concentration of E2 in the sample isolated from
the patient is below the E2 reference range.
[0337] In some embodiments, the GnRH antagonist is selected from
the group consisting of elagolix, relugolix, ASP-1707, SKI2670, and
BAY-784.
[0338] In some embodiments, the GnRH antagonist is elagolix or a
derivative or variant thereof, such as a compound described in U.S.
Pat. No. 7,056,927; 7,176,211; 7,419,983; 8,765,948; or 9,382,214;
or in US Patent Application Publication No. 2014/0288031 or
2017/0056403, the disclosures of which are incorporated herein by
reference in their entirety. In some embodiments, the method
includes administering 150 mg/day or more (e.g., 155 mg/day, 160
mg/day, 165 mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day,
190 mg/day, 195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, 215
mg/day, 220 mg/day, 225 mg/day, 230 mg/day, 235 mg/day, 240 mg/day,
245 mg/day, 250 mg/day, 255 mg/day, 260 mg/day, 265 mg/day, 270
mg/day, 275 mg/day, 280 mg/day, 285 mg/day, 290 mg/day, 295 mg/day,
300 mg/day, 305 mg/day, 310 mg/day, 315 mg/day, 320 mg/day, 325
mg/day, 330 mg/day, 335 mg/day, 340 mg/day, 345 mg/day, 350 mg/day,
355 mg/day, 360 mg/day, 365 mg/day, 370 mg/day, 375 mg/day, 380
mg/day, 385 mg/day, 390 mg/day, 395, 400 mg/day, or more) of
elagolix to the patient if the concentration of E2 in the sample
isolated from the patient is above the E2 reference range. In some
embodiments, the method includes administering from 155 mg/day to
395 mg/day of elagolix to the patient if the concentration of E2 in
the sample isolated from the patient is above the E2 reference
range.
[0339] In some embodiments, the method includes administering 400
mg/day or more (e.g., 400 mg/day, 405 mg/day, 410 mg/day, 415
mg/day, 420 mg/day, 425 mg/day, 430 mg/day, 435 mg/day, 440 mg/day,
445 mg/day, 450 mg/day, 455 mg/day, 460 mg/day, 465 mg/day, 470
mg/day, 475 mg/day, 480 mg/day, 485 mg/day, 490 mg/day, 495 mg/day,
500 mg/day, 505 mg/day, 510 mg/day, 515 mg/day, 520 mg/day, 525
mg/day, 530 mg/day, 535 mg/day, 540 mg/day, 545 mg/day, 550 mg/day,
555 mg/day, 560 mg/day, 565 mg/day, 570 mg/day, 575 mg/day, 580
mg/day, 585 mg/day, 590 mg/day, 595 mg/day, 600 mg/day, 605 mg/day,
610 mg/day, 615 mg/day, 620 mg/day, 625 mg/day, 630 mg/day, 635
mg/day, 640 mg/day, 645 mg/day, 650 mg/day, 655 mg/day, 660 mg/day,
665 mg/day, 670 mg/day, 675 mg/day, 680 mg/day, 685 mg/day, 690
mg/day, 695 mg/day, 700 mg/day, or more) of elagolix to the patient
if the concentration of E2 in the sample isolated from the patient
is above the E2 reference range. In some embodiments, the method
includes administering from 400 mg/day to 600 mg/day of elagolix to
the patient if the concentration of E2 in the sample isolated from
the patient is above the E2 reference range.
[0340] In some embodiments, the method includes administering 150
mg/day or less (e.g., 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day,
70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day,
100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125
mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, or 150
mg/day) of elagolix to the patient if the concentration of E2 in
the sample isolated from the patient is below the E2 reference
range. In some embodiments, the method includes administering from
50 mg/day to 125 mg/day of elagolix to the patient if the
concentration of E2 in the sample isolated from the patient is
below the E2 reference range. In some embodiments, the method
includes administering 100 mg/day of elagolix to the patient if the
concentration of E2 in the sample isolated from the patient is
below the E2 reference range.
[0341] In some embodiments, the method includes administering 400
mg/day or less (e.g., 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day,
70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day,
100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125
mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day,
155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day, 180
mg/day, 185 mg/day, 190 mg/day, 195 mg/day, 200 mg/day, 205 mg/day,
210 mg/day, 215 mg/day, 220 mg/day, 225 mg/day, 230 mg/day, 235
mg/day, 240 mg/day, 245 mg/day, 250 mg/day, 255 mg/day, 260 mg/day,
265 mg/day, 270 mg/day, 275 mg/day, 280 mg/day, 285 mg/day, 290
mg/day, 295 mg/day, 300 mg/day, 305 mg/day, 310 mg/day, 315 mg/day,
320 mg/day, 325 mg/day, 330 mg/day, 335 mg/day, 340 mg/day, 345
mg/day, 350 mg/day, 355 mg/day, 360 mg/day, 365 mg/day, 370 mg/day,
375 mg/day, 380 mg/day, 385 mg/day, 390 mg/day, or 395 mg/day) of
elagolix to the patient if the concentration of E2 in the sample
isolated from the patient is below the E2 reference range. In some
embodiments, the method includes administering from 150 mg/day to
375 mg/day of elagolix to the patient if the concentration of E2 in
the sample isolated from the patient is below the E2 reference
range. In some embodiments, the method includes administering 150
mg/day of elagolix to the patient if the concentration of E2 in the
sample isolated from the patient is below the E2 reference
range.
[0342] In some embodiments, the method includes administering from
150 mg/day to 400 mg/day (e.g., 150 mg/day, 155 mg/day, 160 mg/day,
165 mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day, 190
mg/day, 195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, 215 mg/day,
220 mg/day, 225 mg/day, 230 mg/day, 235 mg/day, 240 mg/day, 245
mg/day, 250 mg/day, 255 mg/day, 260 mg/day, 265 mg/day, 270 mg/day,
275 mg/day, 280 mg/day, 285 mg/day, 290 mg/day, 295 mg/day, 300
mg/day, 305 mg/day, 310 mg/day, 315 mg/day, 320 mg/day, 325 mg/day,
330 mg/day, 335 mg/day, 340 mg/day, 345 mg/day, 350 mg/day, 355
mg/day, 360 mg/day, 365 mg/day, 370 mg/day, 375 mg/day, 380 mg/day,
385 mg/day, 390 mg/day, 395, or 400 mg/day) of elagolix to the
patient if the concentration of E2 in the sample isolated from the
patient is within the E2 reference range. In some embodiments, the
method includes administering 150 mg/day of elagolix to the patient
if the concentration of E2 in the sample isolated from the patient
is within the E2 reference range. In some embodiments, the method
includes administering 400 mg/day of elagolix to the patient if the
concentration of E2 in the sample isolated from the patient is
within the E2 reference range. For instance, the method may include
administering 200 mg of elagolix to the patient twice daily if the
concentration of E2 in the sample isolated from the patient is
within the E2 reference range.
[0343] In some embodiments, the GnRH antagonist is relugolix or a
derivative or variant thereof, such as a compound described in U.S.
Pat. No. 7,300,935; 8,058,280; 8,735,401; or 9,346,822; or in US
Patent Application Publication No. 2015/0266891, the disclosures of
which are incorporated herein by reference in their entirety. In
some embodiments, the method includes administering 40 mg/day or
more (e.g., from 40 mg/day to 150 mg/day or more, such as 45
mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75
mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105
mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day,
135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day, or more) of
relugolix to the patient if the concentration of E2 in the sample
isolated from the patient is above the E2 reference range. In some
embodiments, the method includes administering from 50 mg/day to 75
mg/day of relugolix to the patient if the concentration of E2 in
the sample isolated from the patient is above the E2 reference
range.
[0344] In some embodiments, the method includes administering 40
mg/day or less (e.g., from 10 mg/day to 40 mg/day, such as 10
mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, or 35 mg/day)
of relugolix to the patient if the concentration of E2 in the
sample isolated from the patient is below the E2 reference range.
In some embodiments, the method includes administering from 10
mg/day to 35 mg/day of relugolix to the patient if the
concentration of E2 in the sample isolated from the patient is
below the E2 reference range.
[0345] In some embodiments, the method includes administering from
35 mg/day to 45 mg/day (e.g., 35 mg/day, 40 mg/day, or 45 mg/day)
of relugolix to the patient if the concentration of E2 in the
sample isolated from the patient is within the E2 reference range.
In some embodiments, the method includes administering 40 mg/day of
relugolix to the patient if the concentration of E2 in the sample
isolated from the patient is within the E2 reference range.
[0346] In some embodiments, the GnRH antagonist is ASP-1707 or a
derivative or variant thereof, such as a compound described in U.S.
Pat. No. 6,960,591; 7,569,688; 7,960,562; or 9,527,818, the
disclosures of which are incorporated herein by reference in their
entirety. In some embodiments, the method includes administering 10
mg/day or more (e.g., from 15 mg/day to 100 mg/day or more, such as
15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day,
45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day,
75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day,
or more) of ASP-1707 to the patient if the concentration of E2 in
the sample isolated from the patient is above the E2 reference
range. In some embodiments, the method includes administering from
15 mg/day to 50 mg/day of ASP-1707 to the patient if the
concentration of E2 in the sample isolated from the patient is
above the E2 reference range.
[0347] In some embodiments, the method includes administering 10
mg/day or less (e.g., from 5 mg/day to 9 mg/day, such as 5 mg/day,
6 mg/day, 7 mg/day, 8 mg/day, or 9 mg/day) of ASP-1707 to the
patient if the concentration of E2 in the sample isolated from the
patient is below the E2 reference range. In some embodiments, the
method includes administering from 5 mg/day to 7.5 mg/day of
ASP-1707 to the patient if the concentration of E2 in the sample
isolated from the patient is below the E2 reference range.
[0348] In some embodiments, the method includes administering from
7.5 mg/day to 15 mg/day (e.g., 7.5 mg/day, 10 mg/day, 12.5 mg/day,
or 15 mg/day) of ASP-1707 to the patient if the concentration of E2
in the sample isolated from the patient is within the E2 reference
range. In some embodiments, the method includes administering 10
mg/day of ASP-1707 to the patient if the concentration of E2 in the
sample isolated from the patient is within the E2 reference
range.
[0349] In some embodiments, the GnRH antagonist is BAY-784 or a
derivative or variant thereof. The GnRH antagonist may be a
compound described in US Patent Application Publication No.
2014/0357655 or 2016/0052936, the disclosures of which are
incorporated herein by reference in their entirety.
[0350] In some embodiment s, the method includes orally
administering the GnRH antagonist to the patient. In some
embodiments, the method includes intravenously administering the
GnRH antagonist to the patient.
[0351] In another aspect, the invention provides a kit that
contains the GnRH antagonist of any of the above aspects or
embodiments of the invention. The kit may further contain one or
more agents capable of detecting E2 and/or a package insert. The
package insert may instruct a user of the kit to perform the method
of any one of the above aspects or embodiments of the
invention.
[0352] In some embodiments, the kit contains one or more agents
capable of detecting a compound selected from the group consisting
of LH and FSH. In some embodiments, the kit includes a
thienopyrimidine GnRH antagonist, such as a compound represented by
formula (II) or the choline salt thereof. In some embodiments, the
kit includes a GnRH antagonist selected from the group consisting
of elagolix, relugolix, ASP-1707, SKI2670, and BAY-784, or a
derivative or variant thereof.
[0353] In yet another aspect, the invention features a method of
treating endometriosis in a patient (e.g., a female human patient,
such as a premenopausal female human patient). In another aspect,
the invention features a method of reducing the concentration of
E2, follicle-stimulating hormone (FSH), and/or luteinizing hormone
(LH) in the blood of a patient (e.g., a female human patient, such
as a premenopausal female human patient). In another aspect, the
invention features a method of reducing pain (e.g.,
endometriosis-associated pain) in a patient (e.g., a female human
patient, such as a premenopausal female human patient). In these
aspects, the method includes administering to the patient a
compound represented by formula (I)
##STR00018##
[0354] wherein ring A is a thiophene ring;
[0355] each R.sup.A is independently a halogen atom, a cyano group,
a nitro group, an optionally substituted lower alkyl group, an
optionally substituted lower alkenyl group, an optionally
substituted lower alkynyl group, a hydroxyiminomethyl group, an
optionally substituted sulfonyl group, an optionally substituted
sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW',
COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3,
CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to
W.sup.3 independently are a hydrogen atom or an optionally
substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind
together with the neighboring nitrogen atom to form an optionally
substituted cyclic amino group;
[0356] m is an integer from 0 to 3;
[0357] ring B is an aryl group or a monocyclic heteroaryl
group;
[0358] each R.sup.B is independently a halogen atom, a cyano group,
an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4,
COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6
independently are a hydrogen atom or an optionally substituted
lower alkyl group, or W.sup.5 and W.sup.6 may bind together with
the neighboring nitrogen atom to form an optionally substituted
cyclic amino group;
[0359] n is an integer from 0 to 2;
[0360] U is a single bond;
[0361] X is a group represented by --S-L-Y, --O-L-Y, --CO-L-Y, or
--SO.sub.2-L-Y, wherein L is an optionally substituted lower
alkylene group;
[0362] Y is a group represented by Z or --NW.sup.7W.sup.8, wherein
W.sup.7 and W.sup.8 independently are a hydrogen atom, an
optionally substituted lower alkyl group, or Z with the proviso
that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or
W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen
atom to form an optionally substituted cyclic amino group;
[0363] Z is an optionally fused and optionally substituted
cycloalkyl group, an optionally fused and optionally substituted
heterocycloalkyl group, an optionally fused and optionally
substituted aryl group, or an optionally fused and optionally
substituted heteroaryl group;
[0364] or a pharmaceutically acceptable salt thereof, in an amount
of from about 25 mg per dose to about 300 mg per dose (e.g., in an
amount of about 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60
mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105
mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg,
150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190
mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg,
235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275
mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg per dose). In some
embodiments, the compound is administered in an amount of 50 mg per
dose. In some embodiments, the compound is administered in an
amount of 75 mg per dose. In some embodiments, the compound is
administered in an amount of 100 mg per dose. In some embodiments,
the compound is administered in an amount of 200 mg per dose.
[0365] In some embodiments, the compound is administered orally,
for example, in the form of a tablet, capsule, gel cap, powder,
liquid solution, or liquid suspension.
[0366] The compound may be administered to the patient in one or
more doses per 12 hours, 24 hours, 48 hours, 72 hours, week, month,
or year, such as in from 1 to 10 doses per 12 hours (e.g., 1 dose
every 12 hours, 2 doses every 12 hours, 3 doses every 12 hours, 4
doses every 12 hours, 5 doses every 12 hours, 6 doses every 12
hours, 7 doses every 12 hours, 8 doses every 12 hours, 9 doses
every 12 hours, or 10 doses every 12 hours), from 1 to 10 doses per
24 hours (e.g., 1 dose every 24 hours, 2 doses every 24 hours, 3
doses every 24 hours, 4 doses every 24 hours, 5 doses every 24
hours, 6 doses every 24 hours, 7 doses every 24 hours, 8 doses
every 24 hours, 9 doses every 24 hours, or 10 doses every 24
hours), from 1 to 10 doses per 48 hours (e.g., 1 dose every 48
hours, 2 doses every 48 hours, 3 doses every 48 hours, 4 doses
every 48 hours, 5 doses every 48 hours, 6 doses every 48 hours, 7
doses every 48 hours, 8 doses every 48 hours, 9 doses every 48
hours, or 10 doses every 48 hours), from 1 to 10 doses per 72 hours
(e.g., 1 dose every 72 hours, 2 doses every 72 hours, 3 doses every
72 hours, 4 doses every 72 hours, 5 doses every 72 hours, 6 doses
every 72 hours, 7 doses every 72 hours, 8 doses every 72 hours, 9
doses every 72 hours, or 10 doses every 72 hours), from 1 to 10
doses per week (e.g., 1 dose every week, 2 doses every week, 3
doses every week, 4 doses every week, 5 doses every week, 6 doses
every week, 7 doses every week, 8 doses every week, 9 doses every
week, or 10 doses every week), or from 1 to 60 doses per month
(e.g., from 30-60 doses per month, such as 1 time daily, 2 times
daily, 3 times daily, 4 times daily, 5 times daily, 6 times daily,
7 times daily, 8 times daily, 9 times daily, 10 times daily, 7
times weekly, 8 times weekly, 9 times weekly, 10 times weekly, 11
times weekly, 12 times weekly, 13 times weekly, 14 times weekly, or
more), among others.
[0367] In some embodiments, the compound is administered to the
patient in an amount of about 200 mg/day (e.g., 200 mg/day). In
some embodiments, the compound is administered to the patient in an
amount of about 400 mg every 48 hours (e.g., 400 mg every 48
hours). In some embodiments, the compound is administered to the
patient in an amount of about 600 mg every 72 hours (e.g., 600 mg
every 72 hours). In some embodiments, the compound is administered
to the patient in an amount of about 1,400 mg/week (e.g., 1,400
mg/week).
[0368] In some embodiments, the compound is administered to the
patient in an amount of about 100 mg every 12 hours (e.g., 100 mg
every 12 hours), in an amount of about 50 mg every 6 hours (e.g.,
50 mg every 6 hours), in an amount of about 33.33 mg every 4 hours
(e.g., 33.33 mg every 4 hours), in an amount of about 25 mg every 3
hours (e.g., 25 mg every 3 hours), or the like, e.g., so as to
achieve an amount of 200 mg/day.
[0369] In some embodiments, the compound is administered to the
patient in an amount of about 100 mg/day (e.g., 100 mg/day). In
some embodiments, the compound is administered to the patient in an
amount of about 200 mg every 48 hours (e.g., 200 mg every 48
hours). In some embodiments, the compound is administered to the
patient in an amount of about 300 mg every 72 hours (e.g., 300 mg
every 72 hours). In some embodiments, the compound is administered
to the patient in an amount of about 700 mg/week (e.g., 700
mg/week).
[0370] In some embodiments, the compound is administered to the
patient in an amount of about 50 mg every 12 hours (e.g., 50 mg
every 12 hours), in an amount of about 25 mg every 6 hours (e.g.,
25 mg every 6 hours), in an amount of about 16.67 mg every 4 hours
(e.g., 16.67 mg every 4 hours), in an amount of about 12.5 mg every
3 hours (e.g., 12.5 mg every 3 hours), or the like, e.g., so as to
achieve an amount of 100 mg/day.
[0371] In some embodiments, the compound is administered to the
patient in an amount of about 50 mg/day (e.g., 50 mg/day). In some
embodiments, the compound is administered to the patient in an
amount of about 100 mg every 48 hours (e.g., 100 mg every 48
hours). In some embodiments, the compound is administered to the
patient in an amount of about 150 mg every 72 hours (e.g., 150 mg
every 72 hours). In some embodiments, the compound is administered
to the patient in an amount of about 350 mg/week (e.g., 350
mg/week).
[0372] In some embodiments, the compound is administered to the
patient in an amount of about 25 mg every 12 hours (e.g., 25 mg
every 12 hours), in an amount of about 12.5 mg every 6 hours (e.g.,
12.5 mg every 6 hours), in an amount of about 8.33 mg every 4 hours
(e.g., 8.33 mg every 4 hours), in an amount of about 6.25 mg every
3 hours (e.g., 6.25 mg every 3 hours), or the like, e.g., so as to
achieve an amount of 50 mg/day.
[0373] In some embodiments, the compound is administered to the
patient in an amount of about 75 mg/day (e.g., 75 mg/day). In some
embodiments, the compound is administered to the patient in an
amount of about 150 mg every 48 hours (e.g., 150 mg every 48
hours). In some embodiments, the compound is administered to the
patient in an amount of about 225 mg every 72 hours (e.g., 225 mg
every 72 hours). In some embodiments, the compound is administered
to the patient in an amount of about 525 mg/week (e.g., 525
mg/week).
[0374] In some embodiments, the compound is administered to the
patient in an amount of about 37.5 mg every 12 hours (e.g., 37.5 mg
every 12 hours), in an amount of about 18.75 mg every 6 hours
(e.g., 18.75 mg every 6 hours), in an amount of about 12.5 mg every
4 hours (e.g., 12.5 mg every 4 hours), in an amount of about 9.375
mg every 3 hours (e.g., 9.375 mg every 3 hours), or the like, e.g.,
so as to achieve an amount of 75 mg/day.
[0375] In some embodiments, the ring A is a thiophene ring
represented by formula (A)
##STR00019##
[0376] In some embodiments, m is 1 or 2. In some embodiments, m is
1. For instance, the ring A may be an optionally substituted
thiophene ring represented by formula (B)
##STR00020##
[0377] Each R.sup.A may independently be, for example, a halogen
atom (e.g., fluorine, chlorine, bromine, or iodine), an optionally
substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3,
wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an
optionally substituted lower alkyl group, or W.sup.2 and W.sup.3
may bind together with the neighboring nitrogen atom to form an
optionally substituted cyclic amino group. In some embodiments,
each R.sup.A is COOH or pharmaceutically acceptable salt
thereof.
[0378] In some embodiments, ring B is an optionally substituted
benzene ring, pyridine ring, or thiophene ring. For instance, ring
B may be represented by a formula selected from the group
consisting of:
##STR00021##
[0379] In some embodiments, n is 1 or 2. For instance, in some
embodiments, n is 1. Ring B may be, for example, represented by a
formula selected from the group consisting of:
##STR00022##
[0380] In some embodiments, each R.sup.B is independently a halogen
atom, an optionally substituted lower alkyl group, or OW.sup.4,
wherein each W.sup.4 is independently a hydrogen atom or an
optionally substituted lower alkyl group. For instance, each
R.sup.B may be independently a fluorine atom, chlorine atom,
bromine atom, methyl group, or methoxy group.
[0381] In some embodiments, U is a single bond. X may be, for
example, a group represented by --O-L-Y. L may be, for example, a
methylene group. In some embodiments, Y is an optionally
substituted benzene ring represented by formula (C)
##STR00023##
[0382] wherein each R.sup.C is independently a halogen atom, an
optionally substituted lower alkyl group, or OW.sup.9, wherein each
W.sup.9 is independently a hydrogen atom or an optionally
substituted lower alkyl group; and
[0383] p is an integer from 0 to 3.
[0384] In some embodiments, Y is a substituted benzene ring
represented by formula (D)
##STR00024##
[0385] In some embodiments, the compound is represented by formula
(II)
##STR00025##
or a pharmaceutically acceptable salt thereof.
[0386] In some embodiments, the compound is the choline salt of the
compound represented by formula (II), i.e., choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate.
[0387] In some embodiments, the GnRH antagonist includes the
compound represented by formula (II) in a crystalline state. In
some embodiments, the compound exhibits characteristic X-ray powder
diffraction peaks at about 7.1.degree. 2.theta., 11.5.degree.
2.theta., 19.4.degree. 2.theta., 20.3.degree. 2.theta.,
21.5.degree. 2.theta., 22.0.degree. 2.theta., 22.6.degree.
2.theta., 23.5.degree. 2.theta., and 26.2.degree. 2.theta.. In some
embodiments, the compound exhibits .sup.13C solid-state NMR peaks
centered at about 155.8 ppm, 149.8 ppm, 145.3 ppm, 118.0 ppm, 113.7
ppm, 111.6 ppm, 110.3 ppm, 98.1 ppm, 69.8 ppm, 58.7 ppm, 57.1 ppm,
and 55.5 ppm. In some embodiments, the compound exhibits .sup.19F
solid-state NMR peaks centered at about -131.6 ppm, -145.2 ppm, and
-151.8 ppm.
[0388] In some embodiments, the method includes administering
add-back therapy to the patient. The add-back therapy may be
administered to the patient concurrently with the GnRH antagonist,
prior to administration of the GnRH antagonist, or following
administration of the GnRH antagonist. In some embodiments,
add-back therapy is administered as a fixed dose combination
containing a GnRH antagonist, estrogen, and one or more additional
agents, such as a progestin, in a single pharmaceutical
composition. For instance, add-back therapy may be administered as
a fixed dose combination of a GnRH antagonist, estrogen (e.g., in
the form of .beta.17-estradiol, ethinyl estradiol, or a conjugated
estrogen, such as a conjugated equine estrogen) and/or a progestin
(e.g., norethindrone or a compound that is metabolized in vivo to
produce norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate (also referred to herein as "NETA"), among
other agents, such as progesterone, norgestimate,
medroxyprogesterone, and drospirenone) in the form of a single
pharmaceutical composition, such as a single tablet, capsule, gel
cap, powder, liquid solution, or liquid suspension. In some
embodiments, the add-back therapy is administered orally,
transdermally, or intravaginally.
[0389] In some embodiments, the add-back therapy is administered to
the patient in one or more doses per day, week, month, or year,
such as daily, for example, from 1 to 10 times daily, or more
(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, times daily). In
some embodiments, the add-back therapy is administered to the
patient once daily, for example, concurrently with the GnRH
antagonist. For example, the GnRH antagonist may be administered to
the patient orally, and concurrently with oral administration of
the GnRH antagonist, the add-back therapy may be administered to
the patient orally, transdermally, or intravaginally. In some
embodiments, the add-back therapy is administered to the patient in
the form of a pharmaceutical composition that further includes the
GnRH antagonist, such as a single tablet, capsule, gel cap, powder,
liquid solution, or liquid suspension, for instance, as described
above and herein.
[0390] In some embodiments, the add-back therapy is administered to
the patient once daily, following administration of the compound.
For example, the GnRH antagonist may be administered to the patient
orally, and following oral administration of the GnRH antagonist,
the add-back therapy may be administered to the patient orally,
transdermally, or intravaginally.
[0391] In some embodiments, the add-back therapy is administered to
the patient once daily, prior to administration of the compound.
For example, the GnRH antagonist may be administered to the patient
orally, and prior to oral administration of the GnRH antagonist,
the add-back therapy may be administered to the patient orally,
transdermally, or intravaginally.
[0392] In some embodiments, the add-back therapy includes an
estrogen. In some embodiments, the estrogen is selected from the
group consisting of .beta.17-estradiol, ethinyl estradiol, and
conjugated estrogens, such as conjugated equine estrogens.
[0393] In some embodiments, the estrogen is .beta.17-estradiol. The
.beta.17-estradiol may be administered to the patient, for example,
at a dose of from about 0.1 mg to about 2.5 mg, such as at a dose
of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg,
0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6
mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg,
or 2.5 mg, for instance, by oral administration. In some
embodiments, the .beta.17-estradiol is administered to the patient
at a dose of 1.0 mg, for instance, by oral administration. In some
embodiments, the .beta.17-estradiol is administered to the patient
at a dose of 0.5 mg, for instance, by oral administration.
[0394] The .beta.17-estradiol may be administered to the patient
one or more times per day, week, or month. The .beta.17-estradiol
may be administered to the patient, for example, at a dose of from
about 0.1 mg/day to about 2.5 mg/day, such as at a dose of about
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6
mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day,
1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7
mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2 mg/day,
2.3 mg/day, 2.4 mg/day, or 2.5 mg/day, for instance, by oral
administration. In some embodiments, the .beta.17-estradiol is
administered to the patient ata dose of 1.0 mg/day, for instance,
by oral administration. In some embodiments, the .beta.17-estradiol
is administered to the patient at a dose of 0.5 mg/day, for
instance, by oral administration.
[0395] In some embodiments, the estrogen is ethinyl estradiol. The
ethinyl estradiol may be administered to the patient, for example,
at a dose of from about 1.0 .mu.g to about 6.0 .mu.g, such as at a
dose of about 1.0 .mu.g, 1.1 .mu.g, 1.2 .mu.g, 1.3 .mu.g, 1.4
.mu.g, 1.5 .mu.g, 1.6 .mu.g, 1.7 .mu.g, 1.8 .mu.g, 1.9 .mu.g, 2.0
.mu.g, 2.1 .mu.g, 2.2 .mu.g, 2.3 .mu.g, 2.4 .mu.g, 2.5 .mu.g, 2.6
.mu.g, 2.7 .mu.g, 2.8 .mu.g, 2.9 .mu.g, 3.0 .mu.g, 3.1 .mu.g, 3.2
.mu.g, 3.3 .mu.g, 3.4 .mu.g, 3.5 .mu.g, 3.6 .mu.g, 3.7 .mu.g, 3.8
.mu.g, 3.9 .mu.g, 4.0 .mu.g, 4.1 .mu.g, 4.2 .mu.g, 4.2 .mu.g, 4.3
.mu.g, 4.4 .mu.g, 4.5 .mu.g, 4.6 .mu.g, 4.7 .mu.g, 4.8 .mu.g, 4.9
.mu.g, 5.0 .mu.g, 5.1 .mu.g, 5.2 .mu.g, 5.3 .mu.g, 5.4 .mu.g, 5.5
.mu.g, 5.6 .mu.g, 5.7 .mu.g, 5.8 .mu.g, 5.9 .mu.g, or 6.0 .mu.g,
for instance, by oral administration. In some embodiments, the
ethinyl estradiol is administered to the patient at a dose of 5.0
.mu.g, for instance, by oral administration. In some embodiments,
the ethinyl estradiol is administered to the patient at a dose of
2.5 .mu.g, for instance, by oral administration.
[0396] The ethinyl estradiol may be administered to the patient one
or more times per day, week, or month. The ethinyl estradiol may be
administered to the patient, for example, at a dose of from about
1.0 .mu.g/day to about 6.0 .mu.g/day, such as at a dose of about
1.0 .mu.g/day, 1.1 .mu.g/day, 1.2 .mu.g/day, 1.3 .mu.g/day, 1.4
.mu.g/day, 1.5 .mu.g/day, 1.6 .mu.g/day, 1.7 .mu.g/day, 1.8
.mu.g/day, 1.9 .mu.g/day, 2.0 .mu.g/day, 2.1 .mu.g/day, 2.2
.mu.g/day, 2.3 .mu.g/day, 2.4 .mu.g/day, 2.5 .mu.g/day, 2.6
.mu.g/day, 2.7 .mu.g/day, 2.8 .mu.g/day, 2.9 .mu.g/day, 3.0
.mu.g/day, 3.1 .mu.g/day, 3.2 .mu.g/day, 3.3 .mu.g/day, 3.4
.mu.g/day, 3.5 .mu.g/day, 3.6 .mu.g/day, 3.7 .mu.g/day, 3.8
.mu.g/day, 3.9 .mu.g/day, 4.0 .mu.g/day, 4.1 .mu.g/day, 4.2
.mu.g/day, 4.2 .mu.g/day, 4.3 .mu.g/day, 4.4 .mu.g/day, 4.5
.mu.g/day, 4.6 .mu.g/day, 4.7 .mu.g/day, 4.8 .mu.g/day, 4.9
.mu.g/day, 5.0 .mu.g/day, 5.1 .mu.g/day, 5.2 .mu.g/day, 5.3
.mu.g/day, 5.4 .mu.g/day, 5.5 .mu.g/day, 5.6 .mu.g/day, 5.7
.mu.g/day, 5.8 .mu.g/day, 5.9 .mu.g/day, or 6.0 .mu.g/day, for
instance, by oral administration. In some embodiments, the ethinyl
estradiol is administered to the patient at a dose of 5.0
.mu.g/day, for instance, by oral administration. In some
embodiments, the ethinyl estradiol is administered to the patient
at a dose of 2.5 .mu.g/day, for instance, by oral
administration.
[0397] In some embodiments, the estrogen is a conjugated estrogen,
such as a conjugated equine estrogen. The conjugated estrogen may
be administered to the patient, for example, at a dose of from
about 0.1 mg to about 2.0 mg, such as at a dose of about 0.1 mg,
0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0
mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg,
1.9 mg, or 2.0 mg, for instance, by oral administration. In some
embodiments, the conjugated estrogen is administered to the patient
at a dose of 0.625 mg, for instance, by oral administration. In
some embodiments, the conjugated estrogen is administered to the
patient at a dose of 0.45 mg, for instance, by oral administration.
In some embodiments, the conjugated estrogen is administered to the
patient at a dose of 0.3 mg, for instance, by oral
administration.
[0398] The conjugated estrogen may be administered to the patient
one or more times per day, week, or month. The conjugated estrogen
may be administered to the patient, for example, at a dose of from
about 0.1 mg/day to about 2.0 mg/day, such as at a dose of about
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6
mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day,
1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7
mg/day, 1.8 mg/day, 1.9 mg/day, or 2.0 mg/day, for instance, by
oral administration. In some embodiments, the conjugated estrogen
is administered to the patient at a dose of 0.625 mg/day, for
instance, by oral administration. In some embodiments, the
conjugated estrogen is administered to the patient at a dose of
0.45 mg/day, for instance, by oral administration. In some
embodiments, the conjugated estrogen is administered to the patient
at a dose of 0.3 mg/day, for instance, by oral administration.
[0399] In some embodiments, the add-back therapy includes a
progestin. In some embodiments, the progestin is selected from the
group consisting of norethindrone or an ester thereof, such as
norethindrone acetate, or another agent such as progesterone,
norgestimate, medroxyprogesterone, or drospirenone.
[0400] In some embodiments, the progestin is norethindrone or a
compound that is metabolized in vivo to produce norethindrone, such
as an ester of norethindrone that is de-esterified in vivo to
produce norethindrone, for instance, norethindrone acetate.
[0401] In some embodiments, the progestin is norethindrone. The
norethindrone may be administered to the patient, for example, at a
dose of from about 0.05 mg to about 5.0 mg, such as at a dose of
about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg,
0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1
mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg,
2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8
mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg,
3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5
mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 1.0 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 0.5 mg, for instance, by
oral administration. In some embodiments, the norethindrone is
administered to the patient at a dose of 0.1 mg, for instance, by
oral administration.
[0402] The norethindrone may be administered to the patient one or
more times per day, week, or month. The norethindrone may be
administered to the patient, for example, at a dose of from about
0.05 mg/day to about 5.0 mg/day, such as at a dose of about 0.05
mg/day, 0.06 mg/day, 0.07 mg/day, 0.08 mg/day, 0.09 mg/day, 0.1
mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day,
0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day, 1.2
mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7 mg/day,
1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2 mg/day, 2.3
mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day, 2.7 mg/day, 2.8 mg/day,
2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2 mg/day, 3.3 mg/day, 3.4
mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day, 3.8 mg/day, 3.9 mg/day,
4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3 mg/day, 4.4 mg/day, 4.5
mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day, 4.9 mg/day, or 5.0
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 1.0
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 0.5
mg/day, for instance, by oral administration. In some embodiments,
the norethindrone is administered to the patient at a dose of 0.1
mg/day, for instance, by oral administration.
[0403] In some embodiments, the progestin is norethindrone acetate.
The norethindrone acetate may be administered to the patient, for
example, at a dose of from about 0.05 mg to about 5.0 mg, such as
at a dose of about 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1
mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg,
1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8
mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg,
2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5
mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg,
4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5.0 mg, for
instance, by oral administration. In some embodiments, the
norethindrone acetate is administered to the patient at a dose of
1.0 mg/day, for instance, by oral administration. In some
embodiments, the norethindrone acetate is administered to the
patient at a dose of 0.5 mg, for instance, by oral administration.
In some embodiments, the norethindrone acetate is administered to
the patient at a dose of 0.1 mg, for instance, by oral
administration.
[0404] The norethindrone acetate may be administered to the patient
one or more times per day, week, or month. The norethindrone
acetate may be administered to the patient, for example, at a dose
of from about 0.05 mg/day to about 5.0 mg/day, such as at a dose of
about 0.05 mg/day, 0.06 mg/day, 0.07 mg/day, 0.08 mg/day, 0.09
mg/day, 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day,
0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1
mg/day, 1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day,
1.7 mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1 mg/day, 2.2
mg/day, 2.3 mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day, 2.7 mg/day,
2.8 mg/day, 2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2 mg/day, 3.3
mg/day, 3.4 mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day, 3.8 mg/day,
3.9 mg/day, 4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3 mg/day, 4.4
mg/day, 4.5 mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day, 4.9 mg/day,
or 5.0 mg/day, for instance, by oral administration. In some
embodiments, the norethindrone acetate is administered to the
patient at a dose of 1.0 mg/day, for instance, by oral
administration. In some embodiments, the norethindrone acetate is
administered to the patient at a dose of 0.5 mg/day, for instance,
by oral administration. In some embodiments, the norethindrone
acetate is administered to the patient at a dose of 0.1 mg/day, for
instance, by oral administration.
[0405] In some embodiments, the progestin is progesterone. The
progesterone may be administered to the patient, for example, at a
dose of from about 50 mg to about 250 mg, such as a dose of about
50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95
mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg,
140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180
mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg,
225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg, for instance, by
oral administration. In some embodiments, the progesterone is
administered to the patient at a dose of 200 mg, for instance, by
oral administration. In some embodiments, the progesterone is
administered to the patient at a dose of 100 mg, for instance, by
oral administration.
[0406] The progesterone may be administered to the patient one or
more times per day, week, or month. The progesterone may be
administered to the patient, for example, at a dose of from about
50 mg/day to about 250 mg/day, such as a dose of about 50 mg/day,
55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day,
85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110
mg/day, 115 mg/day, 120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day,
140 mg/day, 145 mg/day, 150 mg/day, 155 mg/day, 160 mg/day, 165
mg/day, 170 mg/day, 175 mg/day, 180 mg/day, 185 mg/day, 190 mg/day,
195 mg/day, 200 mg/day, 205 mg/day, 210 mg/day, 215 mg/day, 220
mg/day, 225 mg/day, 230 mg/day, 235 mg/day, 240 mg/day, 245 mg/day,
or 250 mg/day, for instance, by oral administration. In some
embodiments, the progesterone is administered to the patient at a
dose of 200 mg/day, for instance, by oral administration. In some
embodiments, the progesterone is administered to the patient at a
dose of 100 mg/day, for instance, by oral administration.
[0407] In some embodiments, the progestin is norgestimate. The
norgestimate may be administered to the patient, for example, at a
dose of from about 0.01 mg to about 2.0 mg, such as at a dose of
about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07
mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6
mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg,
1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2.0 mg, for instance, by
oral administration. In some embodiments, the norgestimate is
administered to the patient at a dose of 0.09 mg, for instance, by
oral administration.
[0408] The norgestimate may be administered to the patient one or
more times per day, week, or month. The norgestimate may be
administered to the patient, for example, at a dose of from about
0.01 mg/day to about 2.0 mg/day, such as at a dose of about 0.01
mg/day, 0.02 mg/day, 0.03 mg/day, 0.04 mg/day, 0.05 mg/day, 0.06
mg/day, 0.07 mg/day, 0.08 mg/day, 0.09 mg/day, 0.1 mg/day, 0.2
mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day, 0.7 mg/day,
0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 1.1 mg/day, 1.2 mg/day, 1.3
mg/day, 1.4 mg/day, 1.5 mg/day, 1.6 mg/day, 1.7 mg/day, 1.8 mg/day,
1.9 mg/day, or 2.0 mg/day, for instance, by oral administration. In
some embodiments, the norgestimate is administered to the patient
at a dose of 0.09 mg/day, for instance, by oral administration.
[0409] In some embodiments, the progestin is medroxyprogesterone.
The medroxyprogesterone may be administered to the patient, for
example, at a dose of from about 0.5 mg to about 10.0 mg, such as
at a dose of about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg,
1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9
mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg,
2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6
mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg,
4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3
mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6.0 mg, 6.1 mg,
6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0
mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg,
7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7
mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg,
9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg, for instance, by oral
administration. In some embodiments, the medroxyprogesterone is
administered to the patient at a dose of 5.0 mg, for instance, by
oral administration. In some embodiments, the medroxyprogesterone
is administered to the patient at a dose of 2.5 mg, for instance,
by oral administration. In some embodiments, the
medroxyprogesterone is administered to the patient at a dose of 1.5
mg, for instance, by oral administration.
[0410] The medroxyprogesterone may be administered to the patient
one or more times per day, week, or month. The medroxyprogesterone
may be administered to the patient, for example, at a dose of from
about 0.5 mg/day to about 10.0 mg/day, such as at a dose of about
0.5 mg/day, 0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0
mg/day, 1.1 mg/day, 1.2 mg/day, 1.3 mg/day, 1.4 mg/day, 1.5 mg/day,
1.6 mg/day, 1.7 mg/day, 1.8 mg/day, 1.9 mg/day, 2.0 mg/day, 2.1
mg/day, 2.2 mg/day, 2.3 mg/day, 2.4 mg/day, 2.5 mg/day, 2.6 mg/day,
2.7 mg/day, 2.8 mg/day, 2.9 mg/day, 3.0 mg/day, 3.1 mg/day, 3.2
mg/day, 3.3 mg/day, 3.4 mg/day, 3.5 mg/day, 3.6 mg/day, 3.7 mg/day,
3.8 mg/day, 3.9 mg/day, 4.0 mg/day, 4.1 mg/day, 4.2 mg/day, 4.3
mg/day, 4.4 mg/day, 4.5 mg/day, 4.6 mg/day, 4.7 mg/day, 4.8 mg/day,
4.9 mg/day, 5.0 mg/day, 5.1 mg/day, 5.2 mg/day, 5.3 mg/day, 5.4
mg/day, 5.5 mg/day, 5.6 mg/day, 5.7 mg/day, 5.8 mg/day, 5.9 mg/day,
6.0 mg/day, 6.1 mg/day, 6.2 mg/day, 6.3 mg/day, 6.4 mg/day, 6.5
mg/day, 6.6 mg/day, 6.7 mg/day, 6.8 mg/day, 6.9 mg/day, 7.0 mg/day,
7.1 mg/day, 7.2 mg/day, 7.3 mg/day, 7.4 mg/day, 7.5 mg/day, 7.6
mg/day, 7.7 mg/day, 7.8 mg/day, 7.9 mg/day, 8.0 mg/day, 8.1 mg/day,
8.2 mg/day, 8.3 mg/day, 8.4 mg/day, 8.5 mg/day, 8.6 mg/day, 8.7
mg/day, 8.8 mg/day, 8.9 mg/day, 9.0 mg/day, 9.1 mg/day, 9.2 mg/day,
9.3 mg/day, 9.4 mg/day, 9.5 mg/day, 9.6 mg/day, 9.7 mg/day, 9.8
mg/day, 9.9 mg/day, or 10.0 mg/day, for instance, by oral
administration. In some embodiments, the medroxyprogesterone is
administered to the patient at a dose of 5.0 mg/day, for instance,
by oral administration. In some embodiments, the
medroxyprogesterone is administered to the patient at a dose of 2.5
mg/day, for instance, by oral administration. In some embodiments,
the medroxyprogesterone is administered to the patient at a dose of
1.5 mg/day, for instance, by oral administration.
[0411] In some embodiments, the progestin is drospirenone. The
drospirenone may be administered to the patient, for example, at a
dose of from about 0.1 mg to about 1.0 mg, such as at a dose of
about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8
mg, 0.9 mg, or 1.0 mg, for instance, by oral administration. In
some embodiments, the drospirenone is administered to the patient
at a dose of 0.5 mg, for instance, by oral administration. In some
embodiments, the drospirenone is administered to the patient at a
dose of 0.25 mg, for instance, by oral administration.
[0412] The drospirenone may be administered to the patient one or
more times per day, week, or month. The drospirenone may be
administered to the patient, for example, at a dose of from about
0.1 mg/day to about 1.0 mg/day, such as at a dose of about 0.1
mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day,
0.7 mg/day, 0.8 mg/day, 0.9 mg/day, or 1.0 mg/day, for instance, by
oral administration. In some embodiments, the drospirenone is
administered to the patient at a dose of 0.5 mg/day, for instance,
by oral administration. In some embodiments, the drospirenone is
administered to the patient at a dose of 0.25 mg/day, for instance,
by oral administration.
[0413] In some embodiments, the add-back therapy includes an
estrogen and a progestin. In some embodiments, the add-back therapy
includes .beta.17-estradiol and norethindrone or a compound that is
metabolized in vivo to produce norethindrone, such as an ester of
norethindrone that is de-esterified in vivo to produce
norethindrone, for instance, norethindrone acetate.
[0414] In some embodiments, the add-back therapy includes from
about 0.75 mg to about 1.25 mg of .beta.17-estradiol, e.g.,
administered orally, and from about 0.25 mg to about 0.75 mg of
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate, e.g., administered orally. In some
embodiments, the add-back therapy includes 1.0 mg of
.beta.17-estradiol, e.g., administered orally, and 0.5 mg of
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate, e.g., administered orally. In some
embodiments, the add-back therapy includes 1.0 mg of
.beta.17-estradiol, e.g., administered orally, and, in the same
pharmaceutical composition, 0.5 mg of norethindrone or a compound
that is metabolized in vivo to produce norethindrone, such as an
ester of norethindrone that is de-esterified in vivo to produce
norethindrone, for instance, norethindrone acetate, e.g.,
administered orally. In some embodiments, the add-back therapy
includes 1.0 mg of .beta.17-estradiol, e.g., administered orally,
and, in a separate pharmaceutical composition, 0.5 mg of
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate, e.g., administered orally.
[0415] In some embodiments, the compound is administered to the
patient in a fixed-dose composition that contains about 200 mg of
the compound (e.g., 200 mg of the compound), from about 0.75 mg to
about 1.25 mg of .beta.17-estradiol, and from about 0.25 mg to
about 0.75 mg of norethindrone or a compound that is metabolized in
vivo to produce norethindrone, such as an ester of norethindrone
that is de-esterified in vivo to produce norethindrone, for
instance, norethindrone acetate. In some embodiments, the compound
is administered to the patient in a fixed-dose composition that
contains about 200 mg of the compound (e.g., 200 mg of the
compound), about 1.0 mg of .beta.17-estradiol (e.g., 1.0 mg of
.beta.17-estradiol), and about 0.5 mg of norethindrone or a
compound that is metabolized in vivo to produce norethindrone, such
as an ester of norethindrone that is de-esterified in vivo to
produce norethindrone, for instance, norethindrone acetate (e.g.,
0.5 mg of norethindrone or a compound that is metabolized in vivo
to produce norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate). In some embodiments, the compound is
administered to the patient in a fixed-dose composition that
contains 200 mg of the compound, 1.0 mg of .beta.17-estradiol, and
0.5 mg of norethindrone acetate.
[0416] In some embodiments, the above fixed-dose composition is
administered to the patient in one or more doses per 12 hours, 24
hours, 48 hours, 72 hours, week, month, or year, such as in from 1
to 10 doses per 12 hours (e.g., 1 dose every 12 hours, 2 doses
every 12 hours, 3 doses every 12 hours, 4 doses every 12 hours, 5
doses every 12 hours, 6 doses every 12 hours, 7 doses every 12
hours, 8 doses every 12 hours, 9 doses every 12 hours, or 10 doses
every 12 hours), from 1 to 10 doses per 24 hours (e.g., 1 dose
every 24 hours, 2 doses every 24 hours, 3 doses every 24 hours, 4
doses every 24 hours, 5 doses every 24 hours, 6 doses every 24
hours, 7 doses every 24 hours, 8 doses every 24 hours, 9 doses
every 24 hours, or 10 doses every 24 hours), from 1 to 10 doses per
48 hours (e.g., 1 dose every 48 hours, 2 doses every 48 hours, 3
doses every 48 hours, 4 doses every 48 hours, 5 doses every 48
hours, 6 doses every 48 hours, 7 doses every 48 hours, 8 doses
every 48 hours, 9 doses every 48 hours, or 10 doses every 48
hours), from 1 to 10 doses per 72 hours (e.g., 1 dose every 72
hours, 2 doses every 72 hours, 3 doses every 72 hours, 4 doses
every 72 hours, 5 doses every 72 hours, 6 doses every 72 hours, 7
doses every 72 hours, 8 doses every 72 hours, 9 doses every 72
hours, or 10 doses every 72 hours), from 1 to 10 doses per week
(e.g., 1 dose every week, 2 doses every week, 3 doses every week, 4
doses every week, 5 doses every week, 6 doses every week, 7 doses
every week, 8 doses every week, 9 doses every week, or 10 doses
every week), or from 1 to 60 doses per month (e.g., from 30-60
doses per month, such as 1 time daily, 2 times daily, 3 times
daily, 4 times daily, 5 times daily, 6 times daily, 7 times daily,
8 times daily, 9 times daily, 10 times daily, 7 times weekly, 8
times weekly, 9 times weekly, 10 times weekly, 11 times weekly, 12
times weekly, 13 times weekly, 14 times weekly, or more), among
others. In some embodiments, the above fixed-dose composition is
administered to the patient once daily.
[0417] In some embodiments, the add-back therapy includes from
about 0.25 mg to about 0.75 mg of .beta.17-estradiol, e.g.,
administered orally, and from about 0.05 mg to about 0.2 mg of
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate, e.g., administered orally. In some
embodiments, the add-back therapy includes 0.5 mg of
.beta.17-estradiol, e.g., administered orally, and 0.1 mg of
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate, e.g., administered orally. In some
embodiments, the add-back therapy includes 0.5 mg of
.beta.17-estradiol, e.g., administered orally, and, in the same
pharmaceutical composition, 0.1 mg of norethindrone or a compound
that is metabolized in vivo to produce norethindrone, such as an
ester of norethindrone that is de-esterified in vivo to produce
norethindrone, for instance, norethindrone acetate, e.g.,
administered orally. In some embodiments, the add-back therapy
includes 0.5 mg of .beta.17-estradiol, e.g., administered orally,
and, in a separate pharmaceutical composition, 0.1 mg of
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate, e.g., administered orally.
[0418] In some embodiments, the compound is administered to the
patient in a fixed-dose composition that contains about 200 mg of
the compound (e.g., 200 mg of the compound), from about 0.25 mg to
about 0.75 mg of .beta.17-estradiol, and from about 0.05 mg to
about 0.2 mg of norethindrone or a compound that is metabolized in
vivo to produce norethindrone, such as an ester of norethindrone
that is de-esterified in vivo to produce norethindrone, for
instance, norethindrone acetate. In some embodiments, the compound
is administered to the patient in a fixed-dose composition that
contains about 200 mg of the compound (e.g., 200 mg of the
compound), about 0.5 mg of .beta.17-estradiol (e.g., 0.5 mg of
.beta.17-estradiol), and about 0.1 mg of norethindrone or a
compound that is metabolized in vivo to produce norethindrone, such
as an ester of norethindrone that is de-esterified in vivo to
produce norethindrone, for instance, norethindrone acetate (e.g.,
0.1 mg of norethindrone or a compound that is metabolized in vivo
to produce norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate). In some embodiments, the compound is
administered to the patient in a fixed-dose composition that
contains 200 mg of the compound, 0.5 mg of .beta.17-estradiol, and
0.1 mg of norethindrone acetate.
[0419] In some embodiments, the above fixed-dose composition is
administered to the patient in one or more doses per 12 hours, 24
hours, 48 hours, 72 hours, week, month, or year, such as in from 1
to 10 doses per 12 hours (e.g., 1 dose every 12 hours, 2 doses
every 12 hours, 3 doses every 12 hours, 4 doses every 12 hours, 5
doses every 12 hours, 6 doses every 12 hours, 7 doses every 12
hours, 8 doses every 12 hours, 9 doses every 12 hours, or 10 doses
every 12 hours), from 1 to 10 doses per 24 hours (e.g., 1 dose
every 24 hours, 2 doses every 24 hours, 3 doses every 24 hours, 4
doses every 24 hours, 5 doses every 24 hours, 6 doses every 24
hours, 7 doses every 24 hours, 8 doses every 24 hours, 9 doses
every 24 hours, or 10 doses every 24 hours), from 1 to 10 doses per
48 hours (e.g., 1 dose every 48 hours, 2 doses every 48 hours, 3
doses every 48 hours, 4 doses every 48 hours, 5 doses every 48
hours, 6 doses every 48 hours, 7 doses every 48 hours, 8 doses
every 48 hours, 9 doses every 48 hours, or 10 doses every 48
hours), from 1 to 10 doses per 72 hours (e.g., 1 dose every 72
hours, 2 doses every 72 hours, 3 doses every 72 hours, 4 doses
every 72 hours, 5 doses every 72 hours, 6 doses every 72 hours, 7
doses every 72 hours, 8 doses every 72 hours, 9 doses every 72
hours, or 10 doses every 72 hours), from 1 to 10 doses per week
(e.g., 1 dose every week, 2 doses every week, 3 doses every week, 4
doses every week, 5 doses every week, 6 doses every week, 7 doses
every week, 8 doses every week, 9 doses every week, or 10 doses
every week), from 1 to 60 doses per month (e.g., from 30-60 doses
per month, such as 1 time daily, 2 times daily, 3 times daily, 4
times daily, 5 times daily, 6 times daily, 7 times daily, 8 times
daily, 9 times daily, 10 times daily, 7 times weekly, 8 times
weekly, 9 times weekly, 10 times weekly, 11 times weekly, 12 times
weekly, 13 times weekly, 14 times weekly, or more), among others.
In some embodiments, the fixed-dose composition is administered to
the patient once daily.
[0420] In some embodiments, the patient exhibits a serum
concentration of .beta.17-estradiol that is greater than 20 pg/ml,
greater than 30 pg/ml, greater than 40 pg/ml, or greater than 50
pg/ml prior to the administration of the compound to the patient.
The serum concentration of .beta.17-estradiol may be reduced to
less than 50 pg/ml following administration of the compound to the
patient. For instance, in some embodiments, the patient exhibits a
serum concentration of .beta.17-estradiol that is reduced to less
than 50 pg/ml, less than 45 pg/ml, less than 40 pg/ml, less than 35
pg/ml, less than 30 pg/ml, less than 25 pg/ml, less than 20 pg/ml,
less than 15 pg/ml, or less than 10 pg/ml following administration
of the compound to the patient. In some embodiments, the patient
exhibits a serum concentration of .beta.17-estradiol that is
reduced to less than 10 pg/ml to about 40 pg/ml, such as a serum
concentration of .beta.17-estradiol of 5 pg/ml, 10 pg/ml, 15 pg/ml,
20 pg/ml, 25 pg/ml, 30 pg/ml, 35 pg/ml, or 40 pg/ml. In some
embodiments, the patient exhibits a serum concentration of
.beta.17-estradiol of from 5 pg/ml to 50 pg/ml following
administration of the compound to the patient (e.g., a serum
concentration of .beta.17-estradiol of 5 pg/ml, 6 pg/ml, 7 pg/ml, 8
pg/ml, 9 pg/ml, 10 pg/ml, 11 pg/ml, 12 pg/ml, 13 pg/ml, 14 pg/ml,
15 pg/ml, 16 pg/ml, 17 pg/ml, 18 pg/ml, 19 pg/ml, 20 pg/ml, 21
pg/ml, 22 pg/ml, 23 pg/ml, 24 pg/ml, 25 pg/ml, 26 pg/ml, 27 pg/ml,
28 pg/ml, 29 pg/ml, 30 pg/ml, 31 pg/ml, 32 pg/ml, 33 pg/ml, 34
pg/ml, 35 pg/ml, 36 pg/ml, 37 pg/ml, 38 pg/ml, 39 pg/ml, 40 pg/ml,
41 pg/ml, 42 pg/ml, 43 pg/ml, 44 pg/ml, 45 pg/ml, 46 pg/ml, 47
pg/ml, 48 pg/ml, 49 pg/ml, or 50 pg/ml). In some embodiments, the
patient exhibits a serum concentration of .beta.17-estradiol of
from 5 pg/ml to 20 pg/ml following administration of the compound
to the patient (e.g., a serum concentration of .beta.17-estradiol
of 5 pg/ml, 6 pg/ml, 7 pg/ml, 8 pg/ml, 9 pg/ml, 10 pg/ml, 11 pg/ml,
12 pg/ml, 13 pg/ml, 14 pg/ml, 15 pg/ml, 16 pg/ml, 17 pg/ml, 18
pg/ml, 19 pg/ml, or 20 pg/ml). In some embodiments, the patient
exhibits a serum concentration of .beta.17-estradiol of from 5
pg/ml to 10 pg/ml following administration of the compound to the
patient (e.g., a serum concentration of .beta.17-estradiol of 5
pg/ml, 6 pg/ml, 7 pg/ml, 8 pg/ml, 9 pg/ml, or 10 pg/ml).
[0421] In some embodiments, the patient exhibits a serum
concentration of .beta.17-estradiol of less than 50 pg/ml, or
within one of the ranges specified above, within about 1 to about
22 days of the first administration of the compound to the patient,
such as within about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days,
7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14
days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21
days, or 22 days, for example within about 8 days to about 15 days,
of the first administration of the compound to the patient.
[0422] In some embodiments, the patient exhibits a serum
concentration of .beta.17-estradiol of less than 20 pg/ml, or
within one of the ranges specified above, within about 1 to about
22 days of the first administration of the compound to the patient,
such as within about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days,
7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14
days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21
days, or 22 days, for example, within about 8 days to about 15
days, of the first administration of the compound to the
patient.
[0423] In some embodiments, the patient exhibits a serum
concentration of .beta.17-estradiol of less than 10 pg/ml, or
within one of the ranges specified above, within about 1 to about
22 days of the first administration of the compound to the patient,
such as within about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days,
7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14
days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21
days, or 22 days, for example, within about 8 days to about 15
days, of the first administration of the compound to the
patient.
[0424] In some embodiments of any of the above-described aspects or
embodiments of the invention, the GnRH antagonist, such as the
compound represented by formula (I), (II), or a pharmaceutically
acceptable salt thereof, such as the choline salt thereof, (e.g.,
and add-back therapy) is administered to the patient daily (e.g.,
once daily and/or in any of the above-specified doses per day) for
one or more treatment cycles. In some embodiments, the GnRH
antagonist (e.g., and add-back therapy) is administered to the
patient daily (e.g., once daily and/or in any of the
above-specified doses per day) for one or more treatment cycles,
each lasting for a period of about 4-72 weeks, or longer. For
instance, the GnRH antagonist (e.g., and add-back therapy) may be
administered to the patient daily (e.g., once daily and/or in any
of the above-specified doses per day) for one or more treatment
cycles, each lasting about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8
weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks,
15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21
weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks,
28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34
weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks,
41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47
weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks,
54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60
weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks,
67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, or
more.
[0425] In some embodiments, the GnRH antagonist (e.g., and add-back
therapy) is administered to the patient for one or more treatment
cycles, each lasting for a period of about 4-64 weeks. For
instance, the GnRH antagonist (e.g., and add-back therapy) may be
administered to the patient daily (e.g., once daily and/or in any
of the above-specified doses per day) for one or more treatment
cycles, each lasting about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8
weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks,
15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21
weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks,
28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34
weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks,
41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47
weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks,
54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60
weeks, 61 weeks, 62 weeks, 63 weeks, or 64 weeks.
[0426] In some embodiments, the GnRH antagonist (e.g., and add-back
therapy) is administered to the patient for one or more treatment
cycles, each lasting for a period of about 4-52 weeks. For
instance, the GnRH antagonist (e.g., and add-back therapy) may be
administered to the patient daily (e.g., once daily and/or in any
of the above-specified doses per day) for one or more treatment
cycles, each lasting about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8
weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks,
15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21
weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks,
28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34
weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks,
41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47
weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks.
[0427] In some embodiments, the GnRH antagonist (e.g., and add-back
therapy) is administered to the patient for one or more treatment
cycles, each lasting for a period of about 4-48 weeks. For
instance, the GnRH antagonist (e.g., and add-back therapy) may be
administered to the patient daily (e.g., once daily and/or in any
of the above-specified doses per day) for one or more treatment
cycles, each lasting about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8
weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks,
15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21
weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks,
28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34
weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks,
41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47
weeks, or 48 weeks.
[0428] In some embodiments, the GnRH antagonist (e.g., and add-back
therapy) is administered to the patient for one or more treatment
cycles, each lasting for a period of about 4-24 weeks. For
instance, the GnRH antagonist (e.g., and add-back therapy) may be
administered to the patient daily (e.g., once daily and/or in any
of the above-specified doses per day) for one or more treatment
cycles, each lasting about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8
weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks,
15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21
weeks, 22 weeks, 23 weeks, or 24 weeks.
[0429] In some embodiments, the GnRH antagonist (e.g., and add-back
therapy) is administered to the patient for one or more treatment
cycles, each lasting for a period of about 4-12 weeks. For
instance, the GnRH antagonist (e.g., and add-back therapy) may be
administered to the patient daily (e.g., once daily and/or in any
of the above-specified doses per day) for one or more treatment
cycles, each lasting about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8
weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks.
[0430] In some embodiments, the GnRH antagonist (e.g., and add-back
therapy) is administered to the patient for one or more treatment
cycles (e.g., daily, such as once daily and/or in any of the
above-specified doses per day), each treatment cycle lasting for a
period of about 4 weeks. In some embodiments, the GnRH antagonist
(e.g., and add-back therapy) is administered to the patient for one
or more treatment cycles (e.g., daily, such as once daily and/or in
any of the above-specified doses per day), each treatment cycle
lasting for a period of about 6 weeks. In some embodiments, the
GnRH antagonist (e.g., and add-back therapy) is administered to the
patient for one or more treatment cycles (e.g., daily, such as once
daily and/or in any of the above-specified doses per day), each
treatment cycle lasting for a period of about 8 weeks. In some
embodiments, the GnRH antagonist (e.g., and add-back therapy) is
administered to the patient for one or more treatment cycles (e.g.,
daily, such as once daily and/or in any of the above-specified
doses per day), each treatment cycle lasting for a period of about
12 weeks. In some embodiments, the GnRH antagonist (e.g., and
add-back therapy) is administered to the patient for one or more
treatment cycles (e.g., daily, such as once daily and/or in any of
the above-specified doses per day), each treatment cycle lasting
for a period of about 24 weeks. In some embodiments, the GnRH
antagonist (e.g., and add-back therapy) is administered to the
patient for one or more treatment cycles (e.g., daily, such as once
daily and/or in any of the above-specified doses per day), each
treatment cycle lasting for a period of about 36 weeks. In some
embodiments, the GnRH antagonist (e.g., and add-back therapy) is
administered to the patient for one or more treatment cycles (e.g.,
daily, such as once daily and/or in any of the above-specified
doses per day), each treatment cycle lasting for a period of about
48 weeks. In some embodiments, the GnRH antagonist (e.g., and
add-back therapy) is administered to the patient for one or more
treatment cycles (e.g., daily, such as once daily and/or in any of
the above-specified doses per day), each treatment cycle lasting
for a period of about 52 weeks. In some embodiments, the GnRH
antagonist (e.g., and add-back therapy) is administered to the
patient for one or more treatment cycles (e.g., daily, such as once
daily and/or in any of the above-specified doses per day), each
treatment cycle lasting for a period of about 64 weeks. In some
embodiments, the GnRH antagonist (e.g., and add-back therapy) is
administered to the patient for one or more treatment cycles (e.g.,
daily, such as once daily and/or in any of the above-specified
doses per day), each treatment cycle lasting for a period of about
72 weeks.
[0431] In another aspect, the invention features a kit that
contains the compound of any of the preceding aspects or
embodiments of the invention. The kit may further contain a package
insert. The package insert may instruct a user of the kit to
perform the method of any one of the above aspects or embodiments
of the invention.
Definitions
[0432] As used herein, the term "about" refers to a value that is
within 10% above or below the value being described.
[0433] As used herein, the term "add-back therapy" refers to the
administration of estrogen during a treatment regimen, such as
treatment with a GnRH antagonist (e.g., on the basis of a patient's
AMH or E2 level as described herein), so as to counteract the side
effects of excessive suppression of estradiol. Such side effects
may include, for example, a reduction in bone mineral density
(BMD). A patient's BMD may be assessed by dual energy X-ray
absorptiometry, for instance, in the spine or femur of the patient.
Add-back therapy may be administered to a patient according to the
methods described herein so as to mitigate a reduction in BMD
caused by the administration of a GnRH antagonist. For instance,
add-back therapy may be administered to a patient undergoing GnRH
antagonist therapy such that the patient does not exhibit a
reduction in BMD of greater than 5% (e.g., no greater than 5%, 4%,
3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%,
or less). Add-back therapy may include estrogen in the form of E2,
and may include one or more additional agents, such as a progestin
(e.g., norethindrone or a compound that is metabolized in vivo to
produce norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate). Add-back therapy may be formulated for oral
administration, such as in the form of a tablet, capsule, gel cap,
powder, liquid solution, or liquid suspension. Add-back therapy may
feature a co-formulation containing estrogen (e.g., in the form of
E2) and an additional agent such as a progestin (e.g.,
norethindrone or a compound that is metabolized in vivo to produce
norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate). For instance, add-back therapy may be
administered to a patient in the form of a single tablet, capsule,
gel cap, powder, liquid solution, or liquid suspension that
contains both estrogen (e.g., in the form of E2) and a progestin
(e.g., norethindrone or a compound that is metabolized in vivo to
produce norethindrone, such as an ester of norethindrone that is
de-esterified in vivo to produce norethindrone, for instance,
norethindrone acetate). In some embodiments, add-back therapy is
administered as a fixed dose combination containing a GnRH
antagonist, estrogen, and one or more additional agents, such as a
progestin, in a single pharmaceutical composition. For instance,
add-back therapy may be administered as a fixed dose combination of
a GnRH antagonist, estrogen (e.g., in the form of E2) and a
progestin (e.g., norethindrone or a compound that is metabolized in
vivo to produce norethindrone, such as an ester of norethindrone
that is de-esterified in vivo to produce norethindrone, for
instance, norethindrone acetate) in the form of a single
pharmaceutical composition, such as a single tablet, capsule, gel
cap, powder, liquid solution, or liquid suspension.
[0434] As used herein, the term "affinity" refers to the strength
of a binding interaction between two molecules, such as a ligand
and a receptor. The term "K", as used herein, is intended to refer
to the inhibition constant of an antagonist for a particular
molecule of interest, and can be expressed as a molar concentration
(M). K values for antagonist-target interactions can be determined,
e.g., using methods established in the art. Methods that can be
used to determine the K.sub.i of an antagonist for a molecular
target include competitive binding experiments, e.g., as described
in U.S. Pat. No. 9,040,693. The term "K.sub.d", as used herein, is
intended to refer to the dissociation constant, which can be
obtained, e.g., from the ratio of the rate constant for the
dissociation of the two molecules (k.sub.d) to the rate constant
for the association of the two molecules (k.sub.a) and is expressed
as a molar concentration (M). K.sub.d values for receptor-ligand
interactions can be determined, e.g., using methods established in
the art. Methods that can be used to determine the K.sub.d of a
receptor-ligand interaction include surface plasmon resonance,
e.g., through the use of a biosensor system such as a BIACORE.RTM.
system.
[0435] As used herein, the term "anti-Mullerian hormone reference
range" or "AMH reference range" refers to a range of concentrations
of AMH present within a mammalian subject (e.g., a human subject)
or within a sample isolated there from that indicates that the
subject is fertile or exhibits an ovarian reserve capable of
supporting pregnancy. In some embodiments of the invention, the AMH
reference range is from 15 to 35 pM (e.g., from 15 to 25 pM, from
20 to 30 pM, or from 25 to 35 pM, such as from 16 to 34 pM, from 17
to 33 pM, from 18 to 32 pM, from 19 to 31 pM, from 20-30 pM, from
21 to 29 pM, from 22 to 28 pM, from 23 to 27 pM, or from 24 to 26
pM).
[0436] As used herein, the term ".beta.17-estradiol reference
range" or "E2 reference range" refers to a range of concentrations
of E2 present within a mammalian subject (e.g., a human subject)
that has previously undergone treatment for endometriosis, e.g.,
with a GnRH antagonist, or within a sample isolated there from. An
E2 reference range may be from, e.g., 20 to 50 pg/ml (e.g., from 20
to 40 pg/ml, from 30 to 50 pg/ml, or from 25 to 45 pg/ml, such as
from 21 to 49 pg/ml, from 22 to 48 pg/ml, from 23 to 47 pg/ml, from
24 to 46 pg/ml, from 25 to 45 pg/ml, from 26 to 44 pg/ml, from 27
to 43 pg/ml, from 28 to 42 pg/ml, from 29 to 41 pg/ml, from 30 to
40 pg/ml, from 31 to 39 pm/ml, from 32 to 38 pg/ml, from 33 to 37
pg/ml, or from 34 to 36 pg/ml).
[0437] As used herein, the term "Biberoglu and Behrman scale" or
"B&B scale" refers to a multi-point scale that can be used to
indicate the severity of one or more symptoms experienced by
patient suffering from endometriosis. A B&B score can be
assessed by verbally prompting the patient to indicate the degree
of function or quality of life being experienced. A B&B score
can be used, e.g., to assess the severity of such symptoms as
dysmenorrhea, dyspareunia, chronic pelvic pain, pelvic tenderness,
and induration, among others. Methods of determining a B&B
score are described in detail, e.g., in Vincent et al., Fertility
and Sterility 93:62-67 (2010).
[0438] As used herein, the term "crystalline" or "crystalline form"
means having a physical state that is a regular three-dimensional
array of atoms, ions, molecules or molecular assemblies.
Crystalline forms have lattice arrays of building blocks called
asymmetric units that are arranged according to well-defined
symmetries into unit cells that are repeated in three-dimensions.
In contrast, the term "amorphous" or "amorphous form" refers to an
unorganized (no orderly) structure. The physical state of a
therapeutic compound may be determined by exemplary techniques such
as x-ray diffraction, polarized light microscopy and/or
differential scanning calorimetry.
[0439] As used herein, the term "dual energy X-ray absorptiometry"
(DEXA) refers to a spectroscopic method of measuring bone mineral
density in a patient (e.g., a human patient) in which X-ray
radiation of two distinct frequencies are transmitted towards a
target bone of the patient. The absorption of the transmitted
radiation can subsequently be correlated with a measure of the bone
mineral density within the target bone. Methods of determining bone
mineral density using DEXA are described in detail, e.g., in Mazess
et al., American Journal of Clinical Nutrition 51:1106-1112
(1990).
[0440] As used herein, the term "endogenous" describes a molecule
(e.g., a polypeptide, nucleic acid, or cofactor) that is found
naturally in a particular organism (e.g., a human) or in a
particular location within an organism (e.g., an organ, a tissue,
or a cell, such as a human cell).
[0441] As used herein, the term "Endometriosis Health Profile-5" or
"EHP-5" refers to a questionnaire that can be used to evaluate
quality of life in patient suffering from endometriosis. A score
obtained from this questionnaire (i.e., an "EFP-5 score") may
provide an indication of the patient's degree of pain, feeling of
control and powerlessness, emotional well-being, social support,
and/or self-image. The EHP-5 questionnaire and scores obtained
there from are described in detail, e.g., in Renouvel et al.,
Journal de Gynecologie Obstetrique et Biologie de la Reproduction
38:404-410 (2009).
[0442] As used herein, the term "exogenous" describes a molecule
(e.g., a polypeptide, nucleic acid, or cofactor) that is not found
naturally in a particular organism (e.g., a human) or in a
particular location within an organism (e.g., an organ, a tissue,
or a cell, such as a human cell). Exogenous materials include those
that are provided from an external source to an organism or to
cultured matter extracted there from.
[0443] As used herein, the term "gonadotropin-releasing hormone
antagonist" or "GnRH antagonist" refers to a compound capable of
inhibiting the gonadotropin-releasing hormone receptor, e.g., such
that release of one or more gonadotropins (such as follicle
stimulating hormone and luteinizing hormone) is inhibited. GnRH
antagonists for use with the compositions and methods of the
invention include thieno[3,4d]pyrimidine derivatives and variants,
such as those described in U.S. Pat. No. 9,040,693, the disclosure
of which is incorporated herein by reference in its entirety. For
instance, GnRH antagonists include
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2-
,4-dioxo-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid
or the choline salt thereof, e.g., as described in U.S. Pat. No.
9,169,266, the disclosure of which is incorporated herein by
reference in its entirety. Additional examples of GnRH antagonists
include 2-phenylethylpyrimidine-2,4(1H,3H-dione derivatives and
variants, such as those described in U.S. Pat. Nos. 7,056,927;
7,176,211; and 7,419,983; the disclosures of each of which are
incorporated herein by reference in their entirety. Exemplary GnRH
antagonists include elagolix, relugolix, ASP-1707, SK12670, and
BAY-784, among others, such as those described herein.
[0444] As used herein, the term "IC.sub.50" refers to the
concentration of a substance (antagonist) that reduces the efficacy
of a reference agonist or the constitutive activity of a biological
target by 50%, e.g., as measured in a competitive ligand binding
assay. Exemplary competitive ligand binding assays include
competitive radioligand binding assays, competitive enzyme-linked
immunosorbant assays (ELISA), and fluorescence anisotropy-based
assays, among others known in the art.
[0445] As used herein, the term "Numerical Rating Score" (NRS)
refers to a score within an 11-point numerical scale of 0-10 that
indicates the degree of pain experienced by a patient. For
instance, a score of 0 may indicate the patient is experiencing no
pain, while scores from 1-3 may indicate that the patient is
experiencing mild pain. A score of from 4-6 may indicate that the
patient is experiencing moderate pain, and a score of from 7-10 may
indicate that the patient is experiencing severe pain. Typically,
to determine a NRS score, the patient is asked to indicate the
level of pain currently being experienced, as well as the pain
experienced at its most intense and least intense occurrences.
Methods for determining a NRS are described in detail, e.g., in
McCaffery et al., Pain: Clinical Manual for Nursing Practice.
Baltimore (1993).
[0446] As used herein, the term "pharmaceutical composition" means
a mixture containing a therapeutic compound to be administered to a
subject, such as a mammal, e.g., a human, in order to prevent,
treat or control a particular disease or condition affecting the
mammal, such as endometriosis.
[0447] As used herein, the term "pharmaceutically acceptable"
refers to those compounds, materials, compositions and/or dosage
forms, which are suitable for contact with the tissues of a
subject, such as a mammal (e.g., a human) without excessive
toxicity, irritation, allergic response and other problem
complications commensurate with a reasonable benefit/risk
ratio.
[0448] As used herein, the term "sample" refers to a specimen
(e.g., blood, blood component (e.g., serum or plasma), urine,
saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g.,
placental or dermal), pancreatic fluid, chorionic villus sample,
and cells) isolated from a subject.
[0449] As used herein, the phrases "specifically binds" and "binds"
refer to a binding reaction which is determinative of the presence
of a particular protein in a heterogeneous population of proteins
and other biological molecules that is recognized, e.g., by a
ligand with particularity. A ligand (e.g., a protein, proteoglycan,
or glycosaminoglycan) that specifically binds to a protein will
bind to the protein, e.g., with a K.sub.D of less than 100 nM. For
example, a ligand that specifically binds to a protein may bind to
the protein with a K.sub.D of up to 100 nM (e.g., between 1 pM and
100 nM). A ligand that does not exhibit specific binding to a
protein or a domain thereof may exhibit a K.sub.D of greater than
100 nM (e.g., greater than 200 nM, 300 nM, 400 nM, 500 nM, 600 nm,
700 nM, 800 nM, 900 nM, 1 .mu.M, 100 .mu.M, 500 .mu.M, or 1 mM) for
that particular protein or domain thereof. A variety of assay
formats may be used to determine the affinity of a ligand for a
specific protein. For example, solid-phase ELISA assays are
routinely used to identify ligands that specifically bind a target
protein. See, e.g., Harlow & Lane, Antibodies, A Laboratory
Manual, Cold Spring Harbor Press, New York (1988) and Harlow &
Lane, Using Antibodies, A Laboratory Manual, Cold Spring Harbor
Press, New York (1999), for a description of assay formats and
conditions that can be used to determine specific protein
binding.
[0450] As used herein, the terms "subject" and "patient" are
interchangeable and refer to an organism that receives treatment
for a particular disease or condition as described herein (such as
endometriosis) or that is diagnosed as having a disease or
condition according to the methods described herein. Examples of
subjects and patients include mammals, such as humans, receiving
treatment for diseases or conditions, for example,
endometriosis.
[0451] As used herein, the terms "treat" or "treatment" refer to
therapeutic treatment, in which the object is to prevent or slow
down (lessen) an undesired physiological change or disorder, such
as the progression of endometriosis. Beneficial or desired clinical
results include, but are not limited to, alleviation of symptoms,
such as endometriosis-associated pain. Those in need of treatment
include, e.g., female subjects already diagnosed as having
endometriosis, as well as those prone to developing this condition.
Indications of successful treatment of endometriosis include a
finding that the patient exhibits a reduction in serum
.beta.17-estradiol concentration, for instance, of from an initial
value that is greater than 50 pg/ml to a final value of from about
20 pg/ml to about 50 pg/ml (e.g., a final value of about 20 pg/ml,
25 pg/ml, 30 pg/ml, 35 pg/ml, 40 pg/ml, 45 pg/ml, or 50 pg/ml) or
less, such as a value of from about 5 pg/ml to about 15 pg/ml
(e.g., a final value of about 5 pg/ml, 6 pg/ml, 7 pg/ml, 8 pg/ml, 9
pg/ml, 10 pg/ml, 11 pg/ml, 12 pg/ml, 13 pg/ml, 14 pg/ml, or 15
pg/ml). Additional indicators of successful treatment of
endometriosis include an observation that a patient experiences
reduced levels of pain following treatment, for instance, with a
GnRH antagonist described herein. Reduced pain may be detected
using any one or more of the pain scales described herein or known
in the art or known in the art.
[0452] As used herein, the term "Verbal Rating Score" (VRS) refers
to a subjective multi-point scale used to indicate the level of
pain being experienced by a patient undergoing therapy or that has
previously undergone therapy for a disease or condition, such as
endometriosis. The VRS may be a five-point scale and can be
assessed by prompting the patient with one or more questions in
order to determine the level of pain currently being experienced by
the patient. Methods for assessing a VRS are described in detail,
e.g., in Jensen et al., Journal of Pain and Symptom Management
41:1073-1093 (2011).
[0453] As used herein in the context of achieving a therapeutic
effect within a certain time period of administering treatment to a
subject, such as the administration of a GnRH antagonist to a
subject having endometriosis, phrases such as "within about 4 weeks
of said administering," "within about 8 weeks of said
administering," "within about 12 weeks of said administering,"
"within about 24 weeks of said administering," "within about 36
weeks of said administering," and the like refer to the achievement
of a therapeutic phenotype within about the indicated time period
as measured from the date of the initial administration of the
particular GnRH antagonist to the subject. Exemplary therapeutic
phenotypes that may be achieved by administration of a GnRH
antagonist to a subject suffering from endometriosis include
reduced E2, LH, and/or FSH concentrations in the blood of the
subject, as well as reduced endometriosis-associated pain. For
instance, a subject is considered to exhibit a reduced E2, LH, or
FSH level "within about 4 to about 36 weeks" of administering a
GnRH antagonist to the subject according to a daily dosing schedule
(e.g., 5 mg/day, 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50
mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 200
mg/day, 300 mg/day, 400 mg/day, or more, as described for various
GnRH antagonists herein) if the subject presents with a diminished
E2, LH, or FSH concentration, respectively (e.g., as assessed in a
sample isolated from the subject), within about 4 weeks to about 36
weeks from the date of the first instance of administration of the
GnRH antagonist to the subject. A subject may be administered, for
example, a GnRH antagonist represented by formula (I), (II), or
(III) described herein at a dosing schedule of, e.g., 50 mg/day, 75
mg/day, or 100 mg/day. The subject is considered to present with a
therapeutic phenotype of interest, such as a reduced E2 level
(e.g., an E2 level of from 20 pg/ml to 50 pg/ml) within about 4
weeks to about 36 weeks of administering the GnRH antagonist to the
subject if the subject presents with the therapeutic phenotype of
interest within about 4 weeks to about 36 weeks from the date of
the first instance of administration of the GnRH antagonist
represented by formula (I), (II), or (III) to the subject.
[0454] As used herein, the term "aryl" refers to an unsaturated
aromatic carbocyclic group of from 6 to 14 carbon atoms having a
single ring (e.g., optionally substituted phenyl) or multiple
condensed rings (e.g., optionally substituted naphthyl). Exemplary
aryl groups include phenyl, naphthyl, phenanthrenyl, and the
like.
[0455] As used herein, the term "cycloalkyl" refers to a monocyclic
cycloalkyl group having from 3 to 8 carbon atoms, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, and the like.
[0456] As used herein, the term "halogen atom" refers to a fluorine
atom, a chlorine atom, a bromine atom, or an iodine atom.
[0457] As used herein, the term "heteroaryl" refers to a monocyclic
heteroaromatic, or a bicyclic or a tricyclic fused-ring
heteroaromatic group. Exemplary heteroaryl groups include
optionally substituted pyridyl, pyrrolyl, furyl, thienyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,
[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl,
benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl,
benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl,
benzoxazolyl, quinolizinyl, quinazolinyl, pthalazinyl,
quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl,
pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl,
tetrazolyl, 5,6,7,8-tetrahydroquinolyl,
5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,
xanthenyl, benzoquinolyl, and the like.
[0458] As used herein, the term "heterocycloalkyl" refers to a 3 to
8-membered heterocycloalkyl group having 1 or more heteroatoms,
such as a nitrogen atom, an oxygen atom, a sulfur atom, and the
like, and optionally having 1 or 2 oxo groups such as pyrrolidinyl,
piperidinyl, oxopiperidinyl, morpholinyl, piperazinyl,
oxopiperazinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl,
thiazepanyl, dioxothiazepanyl, azokanyl, tetrahydrofuranyl,
tetrahydropyranyl, and the like.
[0459] As used herein, the terms "lower alkyl" and "C.sub.1-6
alkyl" refer to an optionally branched alkyl moiety having from 1
to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
tert-pentyl, hexyl, and the like.
[0460] As used herein, the term "lower alkylene" refers to an
optionally branched alkylene group having from 1 to 6 carbon atoms,
such as methylene, ethylene, methylmethylene, trimethylene,
dimethylmethylene, ethylmethylene, methylethylene, propylmethylene,
isopropylmethylene, dimethylethylene, butylmethylene,
ethylmethylmethylene, pentamethylene, diethylmethylene,
dimethyltrimethylene, hexamethylene, diethylethylene and the
like.
[0461] As used herein, the term "lower alkenyl" refers to an
optionally branched alkenyl moiety having from 2 to 6 carbon atoms,
such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl,
2-butenyl, 2-methylallyl, and the like.
[0462] As used herein, the term "lower alkynyl" refers to an
optionally branched alkynyl moiety having from 2 to 6 carbon atoms,
such as ethynyl, 2-propynyl, and the like.
[0463] As used herein, the term "optionally fused" refers to a
cyclic chemical group that may be fused with a ring system, such as
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Exemplary ring
systems that may be fused to an optionally fused chemical group
include, e.g., indolyl, isoindolyl, benzofuranyl, isobenzofuranyl,
benzothiophenyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl,
benzoisothiazolyl, indazolyl, benzimidazolyl, quinolinyl,
isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl,
cinnolinyl, indolizinyl, naphthyridinyl, pteridinyl, indanyl,
naphtyl, 1,2,3,4-tetrahydronaphthyl, indolinyl, isoindolinyl,
2,3,4,5-tetrahydrobenzo[b]oxepinyl,
6,7,8,9-tetrahydro-5H-benzocycloheptenyl, chromanyl, and the
like.
[0464] As used herein, the term "optionally substituted" refers to
a chemical moiety that may have one or more (e.g., 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, or more chemical substituents, such as lower alkyl,
lower alkenyl, lower alkynyl, cycloalkyl, heterocyclolalkyl, aryl,
alkylaryl, heteroaryl, alkylheteroaryl, amino, ammonium, acyl,
acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido,
carbamate, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy,
trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like. An
optionally substituted chemical moiety may contain, e.g.,
neighboring substituents that have undergone ring closure, such as
ring closure of vicinal functional substituents, thus forming,
e.g., lactams, lactones, cyclic anhydrides, acetals, thioacetals,
or aminals formed by ring closure, for instance, in order to
generate protecting group.
[0465] As used herein, the term "sulfinyl" refers to the chemical
moiety "--S(O)--R" in which R represents, e.g., hydrogen, aryl,
heteroaryl, optionally substituted alkyl, optionally substituted
alkenyl, or optionally substituted alkynyl.
[0466] As used herein, the term "sulfonyl" refers to the chemical
moiety "--SO.sub.2--R" in which R represents, e.g., hydrogen, aryl,
heteroaryl, optionally substituted alkyl, optionally substituted
alkenyl, or optionally substituted alkynyl.
BRIEF DESCRIPTION OF THE FIGURES
[0467] FIG. 1 is a graph showing the dose-dependent suppression of
serum .beta.17-estradiol (E2) in a series of human female patients
suffering from endometriosis achieved by various daily doses of the
GnRH antagonist represented by formula (III), herein (choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate). The
patients assessed in this group exhibited an initial serum
concentration of anti-Mullerian hormone (AMH) of less than 15 pM.
Values along the x-axis denote time, in weeks, from the inception
of daily treatment with the GnRH antagonist at the indicated
dosage. Values along the y-axis denote serum E2 concentration in
pg/ml.
[0468] FIG. 2 is a graph showing the dose-dependent suppression of
serum E2 in a series of human female patients suffering from
endometriosis achieved by various daily doses of the GnRH
antagonist represented by formula (III), herein (choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate). The
patients assessed in this group exhibited an initial serum
concentration of AMH of from 15 pm to 35 pM. Values along the
x-axis denote time, in weeks, from the inception of daily treatment
with the GnRH antagonist at the indicated dosage. Values along the
y-axis denote serum E2 concentration in pg/ml.
[0469] FIG. 3 is a graph showing the dose-dependent suppression of
serum E2 in a series of human female patients suffering from
endometriosis achieved by various daily doses of the GnRH
antagonist represented by formula (III), herein (choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate). The
patients assessed in this group exhibited an initial serum
concentration of AMH of greater than 35 pM. Values along the x-axis
denote time, in weeks, from the inception of daily treatment with
the GnRH antagonist at the indicated dosage. Values along the
y-axis denote serum E2 concentration in pg/ml.
DETAILED DESCRIPTION
[0470] The invention provides compositions and methods for the
treatment of endometriosis in a patient, such as a premenopausal
female human patient, using gonadotropin-releasing hormone (GnRH)
receptor antagonists. Using the compositions and methods described
herein, a patient, such as a premenopausal female human patient,
having endometriosis may be administered a GnRH antagonist, such as
a compound of formula (I), (II), or a pharmaceutically acceptable
salt thereof, such as choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate, so as to
treat this disease. Indicators of successful treatment include the
alleviation of symptoms, such as endometriosis-associated pain, and
a finding that the patient's serum concentration of
.beta.17-estradiol (E2) has decreased to within a range of from 20
pg/ml to 50 pg/ml, or less. Particularly, the GnRH antagonist
represented by formula (I), (II), or a pharmaceutically acceptable
salt thereof, such as choline
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylate, may be
administered to a patient in an amount of from about 35 mg/day to
about 215 mg/day, such as in an amount of 50 mg/day, 75 mg/day, 100
mg/day, or 200 mg/day, so as to treat the disease and induce the
phenotypes described above. Using the compositions and methods
described herein, the GnRH antagonist may be administered with or
without add-back therapy. Add-back therapy, such as the combined
use of an estrogen and progestin, may be administered to a patient
in order to prevent a loss in bone mineral density that may
otherwise be associated with reduced serum E2 concentrations.
[0471] The invention additionally features methods of treating
endometriosis in a patient, such as a human patient, by
administration of a GnRH antagonist to the patient in an amount
that can be determined based on the concentration of anti-Mullerian
hormone (AMH) and/or E2 in the patient or a sample (e.g., a serum
sample) isolated therefrom. Using the methods of the invention, a
physician of skill in the art can assess the concentration of AMH
in a sample isolated from a patient in order to determine an
optimal initial dosage of a GnRH antagonist to be administered to a
patient suffering from endometriosis or prone to develop this
condition. One may also use the patient's serum E2 concentration as
a biomarker for determining whether the patient's dosage of the
GnRH antagonist should be titrated up or down once treatment with
the GnRH antagonist is underway.
Treatment of Endometriosis
[0472] GnRH antagonists, such as those described herein, represent
a useful therapeutic paradigm for the treatment of endometriosis.
By attenuating the release of FSH and LH from the anterior
pituitary, GnRH antagonists can be used to suppress the production
of estrogen, thereby reducing the aberrant growth of endometrial
tissue. It has presently been discovered that effective treatment
of endometriosis patients exhibiting elevated levels of endogenous
AMH, such as a concentration in blood of beyond 35 pM, can be
achieved by administration to such patients of an increased dosage
of a GnRH antagonist as compared to the dose that would typically
be prescribed or administered for the treatment of endometriosis.
Examples of typical doses of certain GnRH antagonists for the
treatment of endometriosis are described herein, for instance, in
Table 1, below. According to the methods of the invention, if a
determination is made that the concentration of AMH in a sample
isolated from the patient is elevated, for example, beyond an AMH
reference range (such as from 15 to 35 pM), a physician may
determine that the patient should be administered a higher dosage
of a GnRH antagonist relative to the dose of the GnRH antagonist
that would normally be prescribed or administered to a patient for
the treatment of endometriosis. Likewise, it has been presently
discovered that effective treatment endometriosis in a patient
exhibiting a reduced level of endogenous AMH, such as a blood
concentration of AMH of less than 15 pM, can be achieved by
administration to such patients of a decreased dosage of a GnRH
antagonist as compared to the dose that would typically be
prescribed or administered to a patient for the treatment of
endometriosis. Thus, according to the methods described herein, if
it is determined that the patient's endogenous AMH level is low,
for instance, less than the lower bound of an AMH reference range
(such as from 15 to 35 pM), the physician may determine that the
patient should be administered a lower dosage of a GnRH antagonist
relative to the dose of the GnRH antagonist that would normally be
prescribed or administered to the patient for the treatment of
endometriosis. It has further been presently discovered that
optimal treatment of endometriosis in a patient exhibiting an
endogenous AMH concentration that is within an AMH reference range,
such as an AMH reference range of from 15 pM to 35 pM, can be
achieved by administration to such patients of a dosage of a GnRH
antagonist that would typically be prescribed or administered for
the treatment of endometriosis. For instance, a determination that
the patient's AMH level is within the particular AMH reference
range of from 15 to 35 pM may indicate that the patient is to be
administered an intermediate quantity of a GnRH antagonist, such as
a quantity of a GnRH antagonist set forth in Table 1, below.
[0473] Using the methods of the invention, a physician may
subsequently administer the GnRH antagonist to the patient by a
suitable route, such as orally or intravenously, at the dosage
identified based on the foregoing analysis.
TABLE-US-00001 TABLE 1 Examples of typically administered dosages
of GnRH antagonists Typically administered Additional agent(s)
dosage for the administered in GnRH treatment of combination with
antagonist endometriosis GnRH antagonist Elagolix 150 mg QD or 200
mg BID -- Elagolix Less than 150 mg QD or Rifampin or 200 mg BID
ketoconazole Relugolix 40 mg/day -- ASP-1707 10 mg/day --
[0474] The present invention additionally features methods of
optimizing a dosing regimen for a patient suffering from
endometriosis and currently receiving GnRH antagonist treatment for
the disease by assessing the patient's E2 level during the
treatment and comparing the patient's E2 level to a prior
measurement of the patient's E2 level, such as a measurement
obtained prior to the initiation of therapy. According to the
methods of the invention, a determination that the patient's E2
level has increased during the treatment period (e.g., is currently
above an E2 reference range) may indicate that the patient is to be
administered an elevated dosage of the GnRH antagonist. Similarly,
a determination that the patient's E2 level has decreased during
the treatment period (e.g., is currently below an E2 reference
range) may indicate that the patient is to be administered a
reduced dosage of the GnRH antagonist. A determination that the
patient's E2 level has not changed or has remained within an E2
reference range during the treatment period may indicate that the
patient is to be administered the originally dispensed dosage of
the GnRH antagonist. Using the methods of the invention, a
physician may subsequently administer the GnRH antagonist to the
patient at the dosage identified based on the above analysis.
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo--
1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid
(Compound II)
[0475] The invention is based in part on the discovery that
3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-
-1,2,3,4-tetrahydrothieno[3,4d]pyrimidine-5-carboxylic acid, and
the choline salt thereof, represented by formula (III), below) is
an orally active, non-peptide GnRH antagonist. It has been shown to
suppress the luteinizing hormone (LH) and .beta.17-estradiol (E2)
and to significantly reduce endometriosis-associated pain in
Japanese women at doses between 50 and 200 mg daily with a good
safety and tolerability profile.
##STR00026##
[0476] Compound (II) and the choline salt thereof (compound (III))
can be synthesized, for example, using the methodology described in
WO 2014/042176, the disclosure of which is incorporated herein by
reference in its entirety. An exemplary synthetic scheme that may
be used for the preparation of compound (II) and the choline salt
thereof is shown in Scheme 1, below.
##STR00027##
[0477] wherein R.sup.1 and R.sub.2 are each independently C.sub.1-6
alkoxy groups; LG is a nucleofugal leaving group, such as chlorine
or bromine, among others; R.sub.3 represents an optional
substituent, such as halogen, acyl group, C.sub.1-6 alkyl group, or
a nitro substituent; DMAP denotes N-dimethylaminopyridine; and TEA
denotes trimethylamine.
[0478] Compound (II), as well as the choline salt thereof, exhibit
a high affinity for human GnRH receptor (27.4 nM) and are capable
of significantly suppressing serum LH concentration, E2 secretion,
and the size of endometriotic lesions in various animal models of
endometriosis. Using the methods of the invention, a physician of
skill in the art can determine a dosing regimen for a patient
suffering from endometriosis by analyzing the patient's AMH and/or
E2 levels as described herein. Based on the levels of these
endogenous substances, a physician of skill in the art may
administer a thieno[3,4d]pyrimidine derivative represented by
formula (I), above, such as compound (II) or the choline salt
thereof (compound (III)) to the patient according to a dosing
regimen of the invention.
[0479] For instance, according to the methods of the invention, a
physician of skill in the art may assess a patient's AMH level,
e.g., prior to the initiation of GnRH antagonist therapy. If a
determination is made that the concentration of AMH in a sample
isolated from the patient is elevated, e.g., with respect to an AMH
reference range (such as from 15 to 35 pM), the physician may
determine that the patient should be administered a higher dosage
of a thieno[3,4d]pyrimidine derivative represented by formula (I),
above, such as compound (II) or the choline salt thereof (e.g.,
from 75 to 225 mg/day, such as 75 mg/day, 80 mg/day, 85 mg/day, 90
mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day,
120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145
mg/day, 150 mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day,
175 mg/day, 180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day, 200
mg/day, 205 mg/day, 210 mg/day, 215 mg/day, 220 mg/day, 225 mg/day,
or more). For instance, an elevated AMH level relative to the AMH
reference range may indicate that the patient is to be administered
75 mg/day, 100 mg/day, or 200 mg/day of a thieno[3,4d]pyrimidine
derivative represented by formula (I), above, such as compound (II)
or the choline salt thereof.
[0480] Likewise, if it is determined that the patient's AMH level
is low, e.g., with respect to an AMH reference range (such as from
15 to 35 pM), the physician may determine that the patient should
be administered a lower dosage of a thieno[3,4d]pyrimidine
derivative represented by formula (I), above, such as compound (II)
or the choline salt thereof (e.g., from about 35 mg/day to about
125 mg/day, such as about 35 mg/day, 40 mg/day, 45 mg/day, 50
mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80
mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day,
110 mg/day, 115 mg/day, 120 mg/day, or 125 mg/day). For instance, a
reduced AMH level relative to the AMH reference range may indicate
that the patient is to be administered 50 mg/day, 75 mg/day, or 100
mg/day of a thieno[3,4d]pyrimidine derivative represented by
formula (I), above, such as compound (II) or the choline salt
thereof.
[0481] A determination that the patient's AMH level is within a
particular AMH reference range (such as from 15 to 35 pM) may
indicate that the patient is to be administered an intermediate
quantity of a thieno[3,4d]pyrimidine derivative represented by
formula (I), above, such as compound (II) or the choline salt
thereof (e.g., from about 45 mg/day to about 215 mg/day, such as
about 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70
mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100
mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120 mg/day, 125 mg/day,
130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day, 150 mg/day, 155
mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175 mg/day, 180 mg/day,
185 mg/day, 190 mg/day, 195 mg/day, 200 mg/day, 205 mg/day, 210
mg/day, or 215 mg/day). For instance, a patient AMH level that is
within the AMH reference range may indicate that the patient is to
be administered 50 mg/day, 75 mg/day, 100 mg/day, or 200 mg/day of
a thieno[3,4d]pyrimidine derivative represented by formula (I),
above, such as compound (II) or the choline salt thereof. Using the
methods of the invention, a physician may subsequently administer
the GnRH antagonist to the patient at the dosage identified based
on the above analysis.
[0482] Additionally, using the methods of the invention a physician
of skill in the art may optimize a dosing regimen of a
thieno[3,4d]pyrimidine derivative represented by formula (I),
above, such as compound (II) or the choline salt thereof, for a
patient suffering from endometriosis and currently receiving GnRH
antagonist treatment for the disease. The physician may assess the
patient's E2 level during the treatment and compare the patient's
E2 level to a prior measurement of the patient's E2 level, such as
a measurement obtained prior to the initiation of therapy.
According to the methods of the invention, a determination that the
patient's E2 level has increased during the treatment period (e.g.,
is currently above an E2 reference range) may indicate that the
patient is to be administered an elevated dosage of a
thieno[3,4d]pyrimidine derivative represented by formula (I),
above, such as compound (II) or the choline salt thereof (e.g.,
from 75 to 225 mg/day, such as 75 mg/day, 80 mg/day, 85 mg/day, 90
mg/day, 95 mg/day, 100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day,
120 mg/day, 125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145
mg/day, 150 mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day,
175 mg/day, 180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day, 200
mg/day, 205 mg/day, 210 mg/day, 215 mg/day, 220 mg/day, 225 mg/day,
or more). For instance, an elevated E2 level relative to the E2
reference range may indicate that the patient is to be administered
75 mg/day, 100 mg/day, or 200 mg/day of a thieno[3,4d]pyrimidine
derivative represented by formula (I), above, such as compound (II)
or the choline salt thereof.
[0483] Similarly, a determination that the patient's E2 level has
decreased during the treatment period (e.g., is currently below an
E2 reference range) may indicate that the patient is to be
administered a reduced dosage of a thieno[3,4d]pyrimidine
derivative represented by formula (I), above, such as compound (II)
or the choline salt thereof (e.g., from about 35 mg/day to about
125 mg/day, such as about 35 mg/day, 40 mg/day, 45 mg/day, 50
mg/day, 55 mg/day, 60 mg/day, 65 mg/day, 70 mg/day, 75 mg/day, 80
mg/day, 85 mg/day, 90 mg/day, 95 mg/day, 100 mg/day, 105 mg/day,
110 mg/day, 115 mg/day, 120 mg/day, or 125 mg/day). For instance, a
reduced E2 level relative to the E2 reference range may indicate
that the patient is to be administered 50 mg/day, 75 mg/day, or 100
mg/day of a thieno[3,4d]pyrimidine derivative represented by
formula (I), above, such as compound (II) or the choline salt
thereof.
[0484] A determination that the patient's E2 level has not changed
or has remained within an E2 reference range during the treatment
period may indicate that the patient is to be administered the
originally dispensed dosage of a thieno[3,4d]pyrimidine derivative
represented by formula (I), above, such as compound (II) or the
choline salt thereof (e.g., from about 45 mg/day to about 215
mg/day, such as about 45 mg/day, 50 mg/day, 55 mg/day, 60 mg/day,
65 mg/day, 70 mg/day, 75 mg/day, 80 mg/day, 85 mg/day, 90 mg/day,
95 mg/day, 100 mg/day, 105 mg/day, 110 mg/day, 115 mg/day, 120
mg/day, 125 mg/day, 130 mg/day, 135 mg/day, 140 mg/day, 145 mg/day,
150 mg/day, 155 mg/day, 160 mg/day, 165 mg/day, 170 mg/day, 175
mg/day, 180 mg/day, 185 mg/day, 190 mg/day, 195 mg/day, 200 mg/day,
205 mg/day, 210 mg/day, or 215 mg/day). For instance, a patient E2
level that is within the E2 reference range may indicate that the
patient is to be administered 50 mg/day, 75 mg/day, 100 mg/day, or
200 mg/day of a thieno[3,4d]pyrimidine derivative represented by
formula (I), above, such as compound (II) or the choline salt
thereof.
[0485] Using the methods of the invention, a physician may
subsequently administer the GnRH antagonist to the patient at the
dosage identified based on the above analysis.
Elagolix
[0486] Additional GnRH antagonists that may be used in conjunction
with the compositions and methods described herein include elagolix
(4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-be-
nzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamin-
o)-butyric acid sodium salt), represented by formula (IV), below,
as well as derivatives and variants thereof, such as a compound
described in U.S. Pat. No. 7,056,927; 7,176,211; 7,419,983;
8,765,948; or 9,382,214; or in US Patent Application Publication
No. 2014/0288031 or 2017/0056403, the disclosures of which are
incorporated herein by reference in their entirety.
##STR00028##
[0487] Elagolix can be synthesized, for example, using the
methodology described in U.S. Pat. No. 8,765,948, the disclosure of
which is incorporated herein by reference in its entirety. An
exemplary synthetic scheme that may be used for the preparation of
elagolix is shown in Scheme 2, below.
##STR00029## ##STR00030##
[0488] wherein R.sub.4 and R.sub.5 are each independently hydrogen
or C.sub.1-4 alkyl groups, or R.sub.4 and R.sub.5 combine to form a
C.sub.1-6 heterocycloalkyl ring, Boc denotes a tert-butoxycarbonyl
protecting group; TFA denotes trifluoroacetic acid; and HOMs
denotes methanesulfonic acid.
[0489] Typically prescribed or administered dosages of elagolix for
the treatment of endometriosis include 150 mg/day and 400 mg/day
(e.g., 200 mg BID) as set forth in Table 1, above. Reduced doses of
elagolix may be administered to a patient when elagolix is provided
in combination with a cytochrome P450 isoform 3A4 modulator, such
as rifampin or ketoconazole (as described, for instance, in US
Patent Application Publication No. 2017/0056403, the disclosure of
which is incorporated herein by reference in its entirety). For
instance, when administered in combination with rifampin or
ketoconazole, elagolix may be administered to a patient at a dose
that is reduced relative to 150 mg/day, such as a dose of 50
mg/day, 75 mg/day, 100 mg/day, or 125 mg/day. As another example,
elagolix may be administered in combination with rifampin or
ketoconazole at a dose that is reduced relative to 400 mg/day, such
as a dose of 200 mg/day, 250 mg/day, 300 mg/day, or 350 mg/day.
[0490] It has presently been discovered that such low doses of
elagolix may be used for the treatment of endometriosis when a
patient exhibits a reduced concentration of AMH relative to an AMH
reference range. For example, if a patient presents with an AMH
concentration in a blood sample withdrawn from the patient of less
than 15 pM, according to the methods described herein, the patient
may be effectively treated with a reduced dosage of elagolix
relative to that which would typically administered, e.g., as set
forth in Table 1. For example, under these conditions, a patient
may be administered a lower dose of elagolix, such as a dosage that
is set forth in US Patent Application Publication No. 2017/0056403,
such as a dose of 50 mg/day, 75 mg/day, 100 mg/day, or 125 mg/day,
or a dose of 200 mg/day, 250 mg/day, 300 mg/day, or 350 mg/day.
[0491] Thus, using the methods of the invention, a physician of
skill in the art can determine a dosing regimen for a patient
suffering from endometriosis by analyzing the patient's AMH and/or
E2 levels as described herein. Based on the levels of these
endogenous substances, a physician of skill in the art may
administer elagolix, or a derivative or variant thereof, to the
patient according to a dosing regimen of the invention.
[0492] For instance, according to the methods of the invention, a
physician of skill in the art may assess a patient's AMH level,
e.g., prior to the initiation of GnRH antagonist therapy. If a
determination is made that the concentration of AMH in a sample
isolated from the patient is elevated, for instance, beyond an AMH
reference range (such as from 15 to 35 pM), the physician may
determine that the patient should be administered a higher dosage
of elagolix or a derivative or variant thereof, such as a dosage of
150 mg/day or 400 mg/day or more (e.g., from 125 mg/day to 600
mg/day, such as 125 mg/day, 150 mg/day, 175 mg/day, 200 mg/day, 225
mg/day, 250 mg/day, 275 mg/day, 300 mg/day, 325 mg/day, 350 mg/day,
375 mg/day, 400 mg/day, 425 mg/day, 450 mg/day, 475 mg/day, 500
mg/day, 525 mg/day, 550 mg/day, 575 mg/day, or 600 mg/day, or
more). For instance, an elevated AMH level relative to the AMH
reference range may indicate that the patient is to be administered
a dosage of elagolix of 150 mg/day, 400 mg/day, or more. Likewise,
if it is determined that the patient's AMH level is low, e.g., with
respect to an AMH reference range (such as from 15 to 35 pM), the
physician may determine that the patient should be administered a
lower dosage of elagolix, such as from 50 mg/day to 400 mg/day of
elagolix or a derivative or variant thereof (e.g., 50 mg/day, 100
mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day,
or 400 mg/day). A determination that the patient's AMH level is
within a particular AMH reference range (such as from 15 to 35 pM)
may indicate that the patient is to be administered an intermediate
quantity of elagolix or a derivative or variant thereof, such as
150 mg/day or 400 mg/day (e.g., 200 mg BID). For instance, a
patient AMH level that is within the AMH reference range may
indicate that the patient is to be administered 150 mg/day or 400
mg/day (e.g., 200 mg BID) of elagolix. Using the methods of the
invention, a physician may subsequently administer the GnRH
antagonist to the patient at the dosage identified based on the
above analysis.
[0493] Additionally, using the methods of the invention a physician
of skill in the art may optimize a dosing regimen of elagolix or a
derivative or variant thereof for a patient suffering from
endometriosis and currently receiving GnRH antagonist treatment for
the disease. The physician may assess the patient's E2 level during
the treatment and compare the patient's E2 level to a prior
measurement of the patient's E2 level, such as a measurement
obtained prior to the initiation of therapy. According to the
methods of the invention, a determination that the patient's E2
level has increased during the treatment period (e.g., is currently
above an E2 reference range) may indicate that the patient is to be
administered an elevated dosage of elagolix or a derivative or
variant thereof, such as a dosage of 150 mg/day or 400 mg/day or
more (e.g., from 155 mg/day to 395 mg/day or from 400 mg/day to 600
mg/day). For instance, an elevated E2 level relative to the E2
reference range may indicate that the patient is to be administered
a dosage greater than 150 mg/day or greater than 400 mg/day of
elagolix. Similarly, a determination that the patient's E2 level
has decreased during the treatment period (e.g., is currently below
an E2 reference range) may indicate that the patient is to be
administered a reduced dosage of elagolix or a derivative or
variant thereof, such as from 50 mg/day to 125 mg/day of elagolix
or a derivative or variant thereof. A determination that the
patient's E2 level has not changed or has remained within an E2
reference range during the treatment period may indicate that the
patient is to be administered the originally dispensed dosage of
elagolix or a derivative or variant thereof, such as 150 mg/day or
400 mg/day (e.g., 200 mg BID). For instance, a patient E2 level
that is within the E2 reference range may indicate that the patient
is to be administered 150 mg/day or 400 mg/day (e.g., 200 mg BID)
of elagolix. Using the methods of the invention, a physician may
subsequently administer the GnRH antagonist to the patient at the
dosage identified based on the above analysis.
Relugolix
[0494] Additional GnRH antagonists that may be used in conjunction
with the compositions and methods described herein include
relugolix
(1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-
-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-m-
ethoxyurea or a salt thereof), for instance, as represented by
formula (V), below, as well as derivatives and variants thereof,
such as a compound described in U.S. Pat. No. 7,300,935; 8,058,280;
8,735,401; or 9,346,822; or in US Patent Application Publication
No. 2015/0266891, the disclosures of which are incorporated herein
by reference in their entirety.
##STR00031##
[0495] Relugolix can be synthesized, for example, using the
methodology described in U.S. Pat. No. 8,765,948, the disclosure of
which is incorporated herein by reference in its entirety. An
exemplary one-pot synthetic scheme that may be used for the
preparation of relugolix is shown in Scheme 3, below.
Scheme 3. Exemplary Preparation of Relugolix
##STR00032##
[0497] Using the methods of the invention, a physician of skill in
the art can determine a dosing regimen for a patient suffering from
endometriosis by analyzing the patient's AMH and/or E2 levels as
described herein. Based on the levels of these endogenous
substances, a physician of skill in the art may administer
relugolix, or a derivative or variant thereof, to the patient
according to a dosing regimen of the invention.
[0498] For instance, according to the methods of the invention, a
physician of skill in the art may assess a patient's AMH level,
e.g., prior to the initiation of GnRH antagonist therapy. If a
determination is made that the concentration of AMH in a sample
isolated from the patient is elevated, for instance, beyond an AMH
reference range (such as from 15 to 35 pM), the physician may
determine that the patient should be administered a high dosage of
relugolix or a derivative or variant thereof, such as a dosage that
exceeds 40 mg/day (e.g., from 45 mg/day to 150 mg/day). For
instance, an elevated AMH level relative to the AMH reference range
may indicate that the patient is to be administered a dosage
greater than 40 mg/day of relugolix. Likewise, if it is determined
that the patient's AMH level is low, for instance, with respect to
an AMH reference range (such as from 15 to 35 pM), the physician
may determine that the patient should be administered a low dosage
of relugolix, such as from 10 mg/day to 35 mg/day of relugolix or a
derivative or variant thereof. For instance, a reduced AMH level
relative to the AMH reference range may indicate that the patient
is to be administered from 10 mg/day to 35 mg/day of relugolix. A
determination that the patient's AMH level is within a particular
AMH reference range (such as from 15 to 35 pM) may indicate that
the patient is to be administered an intermediate quantity of
relugolix or a derivative or variant thereof, such as 40 mg/day.
For instance, a patient AMH level that is within the AMH reference
range may indicate that the patient is to be administered 40 mg/day
of relugolix. Using the methods of the invention, a physician may
subsequently administer the GnRH antagonist to the patient at the
dosage identified based on the above analysis.
[0499] Additionally, using the methods of the invention a physician
of skill in the art may optimize a dosing regimen of relugolix or a
derivative or variant thereof for a patient suffering from
endometriosis and currently receiving GnRH antagonist treatment for
the disease. The physician may assess the patient's E2 level during
the treatment and compare the patient's E2 level to a prior
measurement of the patient's E2 level, such as a measurement
obtained prior to the initiation of therapy. According to the
methods of the invention, a determination that the patient's E2
level has increased during the treatment period (e.g., is currently
above an E2 reference range) may indicate that the patient is to be
administered an elevated dosage of relugolix or a derivative or
variant thereof, such as a dosage that exceeds 40 mg/day (e.g.,
from 45 mg/day to 150 mg/day). For instance, an elevated E2 level
relative to the E2 reference range may indicate that the patient is
to be administered a dosage greater than 40 mg/day of relugolix.
Similarly, a determination that the patient's E2 level has
decreased during the treatment period (e.g., is currently below an
E2 reference range) may indicate that the patient is to be
administered a reduced dosage of relugolix or a derivative or
variant thereof, such as from 10 mg/day to 35 mg/day of relugolix
or a derivative or variant thereof. For instance, a reduced E2
level relative to the E2 reference range may indicate that the
patient is to be administered from 10 mg/day to 35 mg/day of
relugolix. A determination that the patient's E2 level has not
changed or has remained within an E2 reference range during the
treatment period may indicate that the patient is to be
administered the originally dispensed dosage of relugolix or a
derivative or variant thereof, such as 40 mg/day. For instance, a
patient E2 level that is within the E2 reference range may indicate
that the patient is to be administered 40 mg/day of relugolix.
Using the methods of the invention, a physician may subsequently
administer the GnRH antagonist to the patient at the dosage
identified based on the above analysis.
Methods of Assessing AMH and E2 Concentrations
[0500] Techniques for determining AMH and E2 concentrations within
a patient or a sample isolated there from are known in the art. For
instance, one of skill in the art can use an immunoassay, such as
an enzymatic immunosorbant assay (ELISA) to quantify the
concentration of AMH or E2 within a sample isolated from a patient
(e.g., a blood sample isolated from the patient). Such techniques
may employ anti-AMH and anti-E2 antibodies, examples of which are
known in the art. For instance, immunoassays for the detection and
quantification of AMH in a sample that generate a colorimetric or
fluorescent signal (e.g., using antibodies conjugated to gold
nanoparticles or fluorescent particles) are known in the art and
are described in detail, e.g., in WO 2013/126517, the disclosure of
which is incorporated herein by reference in its entirety. In such
assays, the analytical signal generated (e.g., UV-Vis absorption,
fluorescence, or chemiluminescence) is proportional to the
approximate concentration of AMH in a sample.
[0501] Methods of determining E2 levels within a patient or a
sample isolated there from are known in the art and may involve,
e.g., competitive immunoassays in which E2 analogs compete with E2
for binding to an anti-E2 antibody. Such competitive binding assays
are described in detail, e.g., in U.S. Pat. No. 6,201,141 and WO
1993/025672, the disclosures of which is incorporated herein by
reference in its entirety.
[0502] In addition to the above, Pandey et al., (Clinica Chimica
Acta 190:175-184 (1990)) have reported an ELISA-based E2
quantitation assay using the conjugate
estradiol-6-(O-carboxymethyl)oxime linked to penicillinase with
anti-estradiol antibody coated wells of a microtiter plate.
Additionally, Maurel et al., (J. Immunolog. Methods 102:165-172
(1987)) have reported an E2-sensitive ELISA that utilizes an
estradiol-6-(O-carboxymethyl)oxime conjugated to
.beta.-galactosidase. De Boever et al., (Clin. Chem. 32:1895-1900
(1986)) reported a chemiluminescence immunoassay for E2
quantification with a sensitivity limit of about 49 pg/mL and an
assay time on the order of ninety minutes. De Lauzon et al., (J.
Immunoassay 10:339-357 (1989)) reported a competitive enzyme
immunoassay for E2 detection using microtiter plate wells coated
with E2 coupled to bovine serum albumin (BSA). Alternatively,
biotinylated anti-E2 antibodies may be utilized followed by a
second incubation with avidin coupled to peroxidase. The
disclosures of each of the foregoing references are incorporated
herein by reference in their entirety.
Add-Back Therapy
[0503] Endogenous estrogens are largely responsible for the
development and maintenance of the female reproductive system and
secondary sexual characteristics. Although circulating estrogens
exist in a dynamic equilibrium of metabolic interconversions,
estradiol is the principal intracellular human estrogen and is
substantially more potent than its metabolites, estrone and
estriol, at the receptor level. The primary source of estrogen in
normally cycling adult women is the ovarian follicle, which
secretes 70 to 500 .mu.g of estradiol daily, depending on the phase
of the menstrual cycle. After menopause, most endogenous estrogen
is produced by conversion of androstenedione, secreted by the
adrenal cortex, to estrone by peripheral tissues. Thus, estrone and
the sulfate conjugated form, estrone sulfate, are the most abundant
circulating estrogens in postmenopausal women. Circulating
estrogens modulate the pituitary secretion of the gonadotropins, LH
and FSH, through a negative feedback mechanism. Estrogens act to
reduce the elevated levels of these hormones seen in postmenopausal
women.
[0504] Among the potential side-effects of GnRH antagonist therapy
is a reduction in bone mineral density due to excessive depletion
of estrogen (Newhall-Perry et al., American Journal of Obstetrics
and Gynecology 173:824-829 (1995)). Reductions in bone mineral
density have led to the development of add-back therapy with
estrogen and/or selected progestins that may be administered
concurrently with GnRH antagonists for reducing such adverse
symptoms and the risk of induced bone disease (Barbieri, American
Journal of Obstetrics and Gynecology 166:740-745 (1992)).
[0505] Progestin compounds, such as norethindrone and esters
thereof (e.g., norethindrone acetate), enhance cellular
differentiation and generally oppose the actions of estrogens by
decreasing estrogen receptor levels, increasing local metabolism of
estrogens to less active metabolites, or inducing gene products
that blunt cellular responses to estrogen. Progestins exert their
effects in target cells by binding to specific progesterone
receptors that interact with progesterone response elements in
target genes. Progesterone receptors have been identified in the
female reproductive tract, breast, pituitary, hypothalamus, and
central nervous system. Progestins produce similar endometrial
changes to those of the naturally occurring hormone progesterone.
Progestins may be